Advances and prospects in cell therapy for cancer: explorations from T cells to stem cells.

Introduction

The global incidence of malignant tumors continues to increase, posing a significant public health challenge. 1 , 2 According to the latest projections from the Global Burden of Disease study, by 2050, the annual number of new cancer cases worldwide is expected to exceed 35 million, with related deaths potentially reaching 18.6 million, representing increases of 60.7% and 74.5%, respectively, compared to 2024 levels. 3 Although traditional treatments such as surgery, radiotherapy, and chemotherapy are widely employed, their efficacy is often limited by issues such as inadequate targeting precision, significant systemic toxicity, a tendency to induce drug resistance, and high tumor recurrence rates. 4 , 5

With the advancement of precision medicine, a new generation of cancer treatment strategies, including antibody-drug conjugates (ADCs), cytokines, immune cell engagers, DNA vaccines, and cell therapy, continues to emerge. 6 – 9 Among these, cell therapy, as a transformative modality, is regarded as an important branch of modern oncology and regenerative medicine because of its high specificity, long-term persistence, and ability to induce immune memory. 10 The scientific origins of this field can be traced back to the 19th century, with Charles-Édouard Brown-Séquard’s preliminary attempts to explore animal testicular extracts to combat aging. 11 The practice of cell therapy in the modern sense began in 1956 with the first successful syngeneic bone marrow transplant performed by E. Donnall Thomas between identical twins (Fig. 1 ). 12 The technology subsequently evolved continuously, gradually expanding to include partially matched donor transplants and significantly broadening the donor pool. In 1985, Rosenberg’s team first reported the use of lymphokine-activated killer (LAK) cells for treating advanced cancer, marking the entry of adoptive cell therapy (ACT) into a phase of systematic clinical research. 13 Building on this foundation, the field continued to expand, culminating in a key breakthrough at the end of the 20th century—the advent of chimeric antigen receptor T (CAR-T) cell therapy. 14 In 2017, the U.S. Food and Drug Administration (FDA) approved the first CAR-T cell therapy, tisagenlecleucel (Kymriah), for the treatment of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), marking the official entry of the cell therapy field into a new stage of clinical translation and industrial development. 15 , 16 Driven by this success, researchers have further committed to extending CAR-T cell therapy to solid tumors and developing intelligent control systems such as bispecific CARs and switchable CARs. 17 , 18 Novel cell therapies, such as CAR-natural killer (CAR-NK) cells and CAR-macrophages (CAR-Ms), have rapidly emerged. 19 Fig. 1 Key milestones and the evolutionary path of cell therapy. Created with BioRender.com

Currently, the spectrum of cell therapies has become increasingly diverse, expanding from early T cell therapies to include multiple types, such as NK cells, macrophages, dendritic cells (DCs), B cells, and stem cells, thereby forming a multilayered therapeutic platform. This review systematically elaborates on the molecular mechanisms of action, the regulation of key signaling pathways, and the latest clinical advances in various therapies ranging from T cells to stem cells. Furthermore, strategies to overcome current therapeutic challenges by integrating gene editing technologies, synthetic biology, multiomics-guided personalized strategies, and rational combination therapy modalities are discussed.

T cell therapies

The pivotal role of T cells in antitumor immunity is indisputable, and ACTs, built upon this foundation, have achieved significant breakthroughs in the field of oncology, demonstrating potent therapeutic potential. Currently, primary T cell-based ACT strategies include CAR-T, T cell receptor-engineered T (TCR-T), tumor-infiltrating lymphocyte (TIL), and gamma delta (γδ) T cell therapies.

CAR-T cell therapy

CAR-T cell therapy is among the most groundbreaking advances in the field of cell therapy over the past decade. Its core principle involves genetically modifying a patient’s autologous T cells to express a CAR capable of specifically recognizing tumor surface antigens, thus redirecting the cytotoxic activity of T cells against tumor cells. 20 , 21

Design and evolution of CAR-T cell structure

The structure of the CAR is the foundation of its function and typically comprises key functional modules such as an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain (Fig. 2 ). 22 The extracellular antigen-recognition module is typically composed of a single-chain variable fragment (scFv), which is formed by fusing the variable regions of the antibody light chain (VL) and heavy chain (VH) via a flexible peptide linker, functioning to specifically bind the target antigen. 23 , 24 The hinge region, connecting the scFv to the transmembrane domain, provides necessary spatial flexibility; its length and composition directly influence the flexibility and epitope accessibility of CARs, making it a critical factor ensuring that the scFv can effectively approach and bind the antigen. 25 The transmembrane domain, often derived from molecules such as CD8 or CD28, primarily functions to anchor the CAR in the T cell membrane while also acting as a structural bridge involved in transducing intracellular signals. 25 Studies indicate that the choice of transmembrane domain also affects the stability of the CAR molecule and its propensity to dimerize. 26 The most crucial component is the intracellular signaling domain, which consists of signaling modules essential for T cell activation. Within it, the CD3ζ chain provides the primary signal for T cell activation; its immunoreceptor tyrosine-based activation motifs (ITAMs) are central to downstream signaling from the TCR. The incorporation of a costimulatory domain (such as CD28 or 4-1BB) provides a secondary activation signal, which can significantly increase the in vivo persistence, proliferative capacity, and cytokine secretion of T cells. 27 , 28 Fig. 2 Structural composition and functional evolution of CAR-T cells. The core structure of a CAR consists of three functional domains: an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. The intracellular domain includes a T cell activation motif (CD3ζ) and costimulatory molecule domains, with design variations that underpin the functional differences among various CAR generations. First-generation CARs contained only the CD3ζ signal, resulting in weak cytotoxicity and poor in vivo persistence due to the absence of costimulation. Second-generation CARs incorporated a single costimulatory domain (e.g., CD28 or 4-1BB), significantly enhancing T cell activation, proliferation, and cytotoxic activity, thereby laying the groundwork for clinical efficacy. Third-generation CARs combined dual costimulatory domains (e.g., CD28 and 4-1BB), improving antitumor potency and persistence through synergistic signaling. Fourth-generation CARs, also known as “TRUCKs” (T cells redirected for universal cytokine-mediated killing), are engineered to secrete immunomodulatory factors (e.g., IL-12) upon activation, aiming to remodel the TME and augment immune responses. Fifth-generation CARs integrate JAK-STAT signaling with costimulatory pathways, facilitating universal signaling synergy and eliciting more robust antitumor activity. FasL Fas ligand, IFN-γ interferon-gamma, IL-2Rβ interleukin-2 receptor beta, JAK Janus kinase, ROS reactive oxygen species, STAT signal transducer and activator of transcription, TAA tumor-associated antigen, TME tumor microenvironment, TNFR1 tumor necrosis factor receptor 1, TNF-α tumor necrosis factor-alpha, TRAIL tumor necrosis factor-related apoptosis-inducing ligand. Created with BioRender.com

The development of CAR-T cell therapy is, in essence, a continuous integration of the progressively deeper understanding of T cell activation dynamics and technological innovation. 29 In 1987, Kuwana et al. first proposed the concept of a chimeric receptor that fuses the variable region of an antibody with the constant region of a TCR. 30 Subsequent work demonstrated that the cytoplasmic domain of the CD3ζ chain is sufficient to couple receptor engagement to intracellular signaling pathways, providing critical mechanistic support for the use of CD3ζ as the core signaling module in later generations of CARs. 31 By 1993, the first-generation CAR structure was formally established, characterized by containing only the CD3ζ intracellular signaling domain. 14 However, clinical trials have revealed its shortcomings in vivo, including poor persistence and an inability to overcome the immunosuppressive tumor microenvironment (TME), leading to limited efficacy. 32 These limitations highlight the critical role of costimulatory signals in full T cell activation. Building on this understanding, second-generation CARs matured in the early 2000s. The incorporation of costimulatory domains such as CD28 or 4-1BB markedly improved the persistence, expansion potential, and killing efficacy of engineered T cells. 33 , 34 CAR-T cells targeting CD19 and CD20 demonstrated remarkable efficacy in R/R B-cell malignancies, directly leading to the approval of the world’s first CAR-T cell product (Kymriah) in 2017, marking the formal entry of this therapy into clinical practice. 35 , 36 To further enhance efficacy, third-generation CARs incorporating multiple costimulatory domains have been designed to synergistically delay T cell exhaustion. 37 Fourth-generation “TRUCK” cells build upon this by introducing inducibly expressed immunomodulatory factors (e.g., IL-12), facilitating localized remodeling of the TME. 38 Fifth-generation designs further incorporate chimeric cytokine receptors (e.g., a truncated IL-2Rβ domain and a STAT3-binding motif), coupling antigen recognition with JAK–STAT pathway activation to increase T cell survival and stemness maintenance (Fig. 2 ). 39 , 40

Application of CAR-T cell therapy in cancer treatment

Since the first CAR-T cell product was approved in 2017, major breakthroughs have been made in the treatment of hematologic malignancies with CAR-T cell therapy. 41 , 42 As of April 2026, the FDA has approved seven CAR-T cell therapies for hematological malignancies, with five targeting CD19 and two targeting B-cell maturation antigen (BCMA). 43 , 44 Furthermore, an additional nine CAR-T products have gained regulatory approval in other countries or regions (Table 1 ). CD19, a specific marker of the B-cell lineage, is a core target for CAR-T cell therapy in B-cell malignancies. 45 , 46 CD19-targeted CAR-T cell products have demonstrated remarkable efficacy in the treatment of various B-cell malignancies, including B-ALL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia (CLL). 47 – 50 Tisagenlecleucel (tisa-cel), the first approved CAR-T cell therapy, induced an initial complete response (CR) rate of 85% and a one-year overall survival (OS) rate of 77.2% in patients with B-ALL. 51 In large B-cell lymphomas such as DLBCL, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have demonstrated efficacy significantly superior to that of conventional chemotherapy. Specifically, axi-cel yielded a CR rate (CRR) of 65% and an 18-month OS rate of 52%, outperforming the standard regimen of chemotherapy combined with autologous stem cell transplantation in the second-line setting and demonstrating advantages in both progression-free survival (PFS) and OS. 35 , 52 Table 1 Approved CAR-T cell therapies for cancer Product name (INN, Brand) Key status Target Developer/Sponsor Approved regions First approval Approved indication(s) Tisagenlecleucel (Kymriah) First FDA-approved CAR-T CD19 Novartis (Global) USA, EU, JP 2017-08-30 (USA) R/R B-ALL (≤25 yr); Adult R/R LBCL Axicabtagene ciloleucel (Yescarta) First CAR-T for DLBCL/LBCL CD19 Kite (Global); Fosun Kite (China) USA, EU, JP, CN 2017-10-18 (USA) Adult R/R LBCL Brexucabtagene autoleucel (Tecartus) – CD19 Kite (Gilead) USA, EU 2020-07-24 (USA) Adult R/R MCL; R/R B-ALL Lisocabtagene maraleucel (Breyanzi) – CD19 Juno/Bristol-Myers Squibb USA, EU, JP 2021-02-05 (USA) Adult R/R LBCL; R/R FL; R/R CLL/SLL Varnimcabtagene autoleucel (ARI-0001; Qartemi) First EU academic CAR-T (Hospital Exemption) CD19 Hospital Clínic de Barcelona (ES); Immuneel Therapeutics (IN) ES, IN 2021-02-10 (ES) Adult R/R B-ALL (>25 yr); Adult R/R B-NHL Idecabtagene vicleucel (Abecma) First FDA-approved BCMA-targeted CAR-T BCMA Celgene/Bristol-Myers Squibb USA, EU, JP 2021-03-26 (USA) R/R MM (≥4 prior lines) Relmacabtagene autoleucel (Carteyva) – CD19 JW Therapeutics (China) CN 2021-09-06 Adult R/R LBCL; R/R FL; Adult R/R MCL Ciltacabtagene autoleucel (Carvykti) First FDA-approved China-developed CAR-T BCMA Janssen (Global); Nanjing Legend (China) USA, EU, JP, CN 2022-02-28 (USA) R/R MM Equecabtagene autoleucel (Fucaso) First fully human BCMA-targeted CAR-T BCMA IASO Bio/Innovent CN 2023-06-30 Adult R/R MM (≥3 prior lines) Talicabtagene autoleucel (NexCAR19) First indigenous CAR-T developed in India CD19 ImmunoACT IN 2023-10-13 Adult R/R B-cell lymphomas and leukemia Inaticabtagene autoleucel (Yuanruida/CNCT19) – CD19 Juventas Cell Therapy CN 2023-11-07 Adult R/R B-ALL Zevorcabtagene autoleucel (Zevor-cel) – BCMA CARsgen Therapeutics CN 2024-03-01 Adult R/R MM (≥3 prior lines) Cesnicabtagene autoleucel (ARI-0002h) First EU BCMA-targeted CAR-T (Hospital Exemption) BCMA Hospital Clínic de Barcelona (ES) ES 2024-07-19 Adult R/R MM Obecabtagene autoleucel (Aucatzyl) – CD19 Autolus USA, EU 2024-11-08 (USA) Adult R/R B-ALL Ranicabtagene autoleucel (HICARA) – CD19 Hengrun Dasheng CN 2025-07-30 Adult R/R LBCL (≥2 prior lines) Pujicabtagene autoleucel (Pulidekai) First CAR-T for pediatric R/R B-ALL in China CD19 Chongqing Precision Biotech CN 2025-11-07 Pediatric CD19 + R/R B-ALL (3–21 yr) B-ALL B-cell acute lymphoblastic leukemia, BCMA B-cell maturation antigen, B-NHL B-cell non-Hodgkin lymphoma, CLL chronic lymphocytic leukemia, CN China, DLBCL diffuse large B-cell lymphoma, ES Spain, EU European Union, FDA Food and Drug Administration, FL follicular lymphoma, IN India, INN International Nonproprietary Name, JP Japan, LBCL large B-cell lymphoma, MCL mantle cell lymphoma, MM multiple myeloma, R/R relapsed/refractory, SLL small lymphocytic lymphoma

The recently approved obecabtagene autoleucel (obe-cel) significantly reduced treatment-related toxicity through its fast-off antigen dissociation mechanism, limiting the incidence of grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) to 2.4% and 7.1%, respectively, making it the first CAR-T cell product to receive an exemption from the FDA’s Risk Evaluation and Mitigation Strategy (REMS) requirements. 53 In the field of multiple myeloma (MM) treatment, BCMA-targeted CAR-T cell therapies have achieved significant results. 54 Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) induced profound and sustained remissions in heavily pretreated (median of 6 prior lines) patients with R/R MM. The former showed a 73% overall response rate and a median PFS (mPFS) of 8.8 months, whereas the latter achieved a 98% response rate and an mPFS of more than 34 months; moreover, 33% of patients showed PFS exceeding 5 years. 54 – 56 Compared to standard treatment regimens, BCMA-targeted CAR-T cell therapy significantly prolongs PFS. 57 , 58 The current research focus is shifting toward expanding the target spectrum and optimizing safety. Novel targets such as CD7, CD123, Siglec-6, GPRC5D, and NKG2D are under investigation in preclinical and clinical studies, potentially expanding CAR-T cell therapy to acute myeloid leukemia (AML), T cell malignancies, and other diseases. 59 – 62

In the field of solid tumor therapy, although CAR-T cell therapy has not yet received formal clinical approval, it has achieved a series of landmark breakthrough advances. 63 Recent research has focused on targets such as Claudin18.2, CD70, glypican-3 (GPC3), carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), interleukin-13 receptor subunit alpha 2 (IL13Rα2), disialoganglioside (GD2), and B7-H3 (Fig. 3 ), demonstrating promising therapeutic potential in various refractory solid tumors, including gastric cancer (GC), liver cancer, neuroblastoma, and glioma (Table 2 ). 64 , 65 In gastrointestinal cancers, CAR-T cell therapy targeting Claudin18.2 has achieved the most notable progress. The results of the first global randomized controlled phase II clinical trial (CT041-ST-01) for solid tumor CAR-T cell therapy demonstrated that satri-cel, targeting Claudin18.2, significantly extended the mPFS (3.25 months vs. 1.77 months) and reduced the risk of progression by 63% compared to standard chemotherapy in pretreated patients with advanced GC and gastroesophageal junction cancer (GEJC). 66 This study also revealed a trend toward improved OS, with a favorable safety profile, a low incidence of severe CRS, and no reports of high-grade neurotoxicity, suggesting its potential as a third-line standard treatment for advanced GC. To address the potential “on-target/off-tumor” toxicity risk associated with Claudin18.2 targeting, recent research has developed low-affinity fully human VH single-domain CAR-T cells, which markedly reduced toxicity to gastric tissue while maintaining antitumor efficacy. 67 Fig. 3 Schematic summary of investigational targets across major cell therapy platforms. The diagram categorizes targets for cell therapies—including CAR-T, TCR-T cells, and CAR-NK cells—by anatomical location and tumor type. AFP alpha-fetoprotein, ALPP alkaline phosphatase, placental type, B7-H3 B7 homolog 3, CAIX carbonic anhydrase IX, CEA carcinoembryonic antigen, EBV LMP1/LMP2A Epstein–Barr virus latent membrane protein 1/2A, EGFR epidermal growth factor receptor, EGFRvIII epidermal growth factor receptor variant III, EphA2 ephrin type-A receptor 2, EpCAM epithelial cell adhesion molecule, FAP fibroblast activation protein, FRα folate receptor alpha, GD2 disialoganglioside 2, GPC3 glypican-3, gp100 glycoprotein 100, GUCY2C guanylate cyclase 2C, HER2 human epidermal growth factor receptor 2, HNSCC head and neck squamous cell carcinoma, HPV E6/E7 human papillomavirus E6/E7, ICAM1 intercellular adhesion molecule 1, IL13Rα2 interleukin-13 receptor subunit alpha 2, KK-LC-1 Kita-kyushu lung cancer antigen 1, MAGE melanoma-associated antigen, MART-1 melanoma antigen recognized by T cells 1, MET mesenchymal-epithelial transition factor, MSLN mesothelin, MUC1/16 mucin 1/16, NKG2DL natural killer group 2D ligands, NY-ESO-1 New York esophageal squamous cell carcinoma 1, PAP prostatic acid phosphatase, PRAME preferentially expressed antigen in melanoma, PSCA prostate stem cell antigen, PSMA prostate-specific membrane antigen, ROBO1 roundabout guidance receptor 1, ROR1 receptor tyrosine kinase-like orphan receptor 1, TAG72 tumor-associated glycoprotein 72, VEGFR vascular endothelial growth factor receptor, WT1 Wilms tumor 1. Created with BioRender.com Table 2 Key clinical trials of CAR-T cell therapy for solid tumors Target NCT number/Registry Cancer type Phase Enrollment ( n ) Key outcomes Ref. Claudin18.2 NCT04581473 G/GEJC II 156 ORR: 22.0%; mPFS: 3.25 mo; mOS: 7.92 mo (vs. control: ORR: 4.0%, mPFS: 1.77 mo, mOS: 5.49 mo) 66 Claudin18.2 NCT03874897 GC I 98 ORR: 38.8%; DCR: 91.8%; mPFS: 4.4 mo; mOS: 8.8 mo; mDoR: 6.4 mo 83 Claudin18.2 NCT03874897 ; NCT04581473 Pancreatic cancer II 24 ORR: 16.7%; DCR: 70.8%; mPFS: 3.3 mo; mOS: 10.0 mo; mDoR: 9.5 mo; CA19-9 reduction ≥30% in 70.8% of patients 63 CD70 NCT04438083 Advanced ccRCC I 16 DCR: 81.3%; 1 CR sustained >3 yr 69 CD70 NCT04696731 Advanced ccRCC I 44 Confirmed ORR (CD70 expression ≥50% cohort): 33.3%. No GvHD was reported. 70 GPC3 NCT05155189 Advanced HCC I 24 ORR: 50.0%; DCR: 90.9%; Median tumor reduction: 44.0%; Grade 3 CRS: 4.2% 71 GPC3 NCT04405778 HCC, GC, liposarcoma I 11 DCR: 45.5%, including 3 patients with durable SD (≥6 mo) 99 IL13Rα2 NCT02208362 Recurrent GBM I 65 8 CR; 32 SD; 25 PD; mOS: 7.7 mo 64 GD2 NCT04196413 Diffuse midline glioma I 13 4 CR; 5 PR; 4 PD 65 CEA NCT06006390 R/R NSCLC I/II 15 7 PR; 6 SD; 2 PD; ORR: 46.7%; DCR: 86.7% 76 CEA NCT02349724 mCRC I 10 DCR: 70.0%, with 2 cases of SD lasting ≥30 wk; no DLT or Grade ≥3 CRS observed 493 EGFR NCT03182816 R/R NSCLC I 9 mPFS: 7.13 mo; mOS: 15.63 mo; Disease progression in 2 patients 494 EGFRvIII NCT02209376 GBM I 10 mOS: 8.0 mo; 1 patient with SD for 18.0 mo 86 HER2 NCT01109095 GBM I 17 7 SD; mOS: 11.1 mo; 3 patients with PFS of 24–29 mo 495 CD19/GCC ChiCTR2000040645 mCRC I 15 ORR: 40.0%; mPFS: 6.0 mo (2 × 10 6 cells/kg dose cohort); mOS: 22.8 mo; mDoR: 5.1 mo 93 CA19-9 carbohydrate antigen 19-9, ccRCC clear cell renal cell carcinoma, CEA carcinoembryonic antigen, ChiCTR Chinese Clinical Trial Registry, CR complete response, CRS cytokine release syndrome, DCR disease control rate, DLT dose-limiting toxicity, EGFR epidermal growth factor receptor, EGFRvIII epidermal growth factor receptor variant III, G/GEJC gastric or gastroesophageal junction cancer, GBM glioblastoma, GC gastric cancer, GCC guanylyl cyclase C, GD2 disialoganglioside 2, GPC3 glypican-3, GvHD graft-versus-host disease, HCC hepatocellular carcinoma, HER2 human epidermal growth factor receptor 2, IL13Rα2 interleukin-13 receptor subunit alpha 2, mCRC metastatic colorectal cancer, mDoR median duration of response, mOS median overall survival, mPFS median progression-free survival, NSCLC non-small cell lung cancer, ORR objective response rate, PD progressive disease, PR partial response, R/R relapsed/refractory, SD stable disease

In renal cell carcinoma (RCC), CD70 has emerged as a promising therapeutic target because of its stable and high expression in both primary and metastatic lesions. 68 Phase I clinical trial data for CTX130, the first allogeneic CAR-T cell therapy targeting CD70, revealed that 81.3% of patients achieved disease control, with no dose-limiting toxicity (DLT) observed, and one patient achieved a sustained CR lasting up to 3 years. 69 At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, the latest reported data for CD70-targeting CAR-T cell therapy ALLO-316 from its phase I study ( NCT04696731 ) revealed an objective response rate (ORR) of 31% in patients with high CD70 expression and demonstrated the potential for durable responses. 70 For hepatocellular carcinoma (HCC), the GPC3-directed CAR-T cell product C-CAR031 exhibited dose-response activity, with an ORR of 57.1% in the high-dose cohort. 71 Notably, GPC3-targeted CAR-T cell therapy combined with local microwave ablation has demonstrated durable efficacy in patients with advanced HCC complicated by inferior vena cava tumor thrombi. Specifically, two patients achieved disease-free survival of 8 and 7 years, providing crucial evidence for the long-term potential of CAR-T cells in treating solid tumors. 72

With respect to nervous system tumors, the intratumoral administration of IL13Rα2-targeting CAR-T cells resulted in a nearly 8-month CR in a patient with recurrent high-grade glioma. 73 Moreover, a bispecific CAR-T cell therapy (CART-EGFR-IL13Rα2) resulted in a 62% tumor regression rate in a phase I trial for EGFR-amplified recurrent glioblastoma (GBM). 74 In a first-in-human study, GD2-directed CAR-T cells exhibited a controllable safety profile and induced significant imaging-based tumor regression in patients with H3K27M-mutant diffuse midline glioma. 75 Our team has demonstrated the promising efficacy and favorable safety of hypoxia-responsive CEA-targeted CAR-T cells in non-small cell lung cancer (NSCLC). In our recent phase I trial, this approach achieved an ORR of 47% and a disease control rate (DCR) of 87%, with no DLTs observed. 76 Furthermore, our single-cell RNA sequencing analysis revealed that the status of NK cells is correlated with the therapeutic response, suggesting a potential immunomodulatory mechanism of this therapy.

The rational selection of target antigens is crucial for dictating the clinical efficacy and safety profile of CAR-T cell therapy in solid tumors. An ideal target must exhibit high tumor selectivity to minimize the risk of life-threatening on-target/off-tumor toxicity. 77 Tumor-specific antigens (TSAs) derived from somatic mutations, such as intracellular neoantigens, theoretically carry a low risk of on-target/off-tumor toxicity and are thus considered ideal targets. 78 However, their broad clinical application has been severely restricted by their profound interpatient and interclonal heterogeneity, the cumbersome and costly nature of personalized manufacturing processes, and their predominantly intracellular localization (which necessitates TCR-like CAR technologies to recognize peptide-HLA complexes). 79 Consequently, tumor-associated antigens (TAAs) have emerged as the primary targeting strategy in current clinical translation. Nevertheless, the clinical translation of certain TAAs has been underwhelming or has failed entirely. A primary reason for this failure is the inadequate management of on-target/off-tumor toxicity risks. The basal expression of TAAs in vital organs, such as the heart, lungs, and brain, constitutes the pathophysiological basis for on-target/off-tumor toxicity. For instance, the low-level baseline expression of mesothelin in nonmalignant pulmonary and pleural epithelia, or its reactive upregulation under pathological conditions such as inflammation, directly precipitated severe respiratory toxicities in early clinical trials. 80 This elucidates why such initially promising targets failed during early CAR-T cell explorations and underscores the absolute necessity of comprehensively and precisely mapping systemic antigen expression profiles.

Target coverage—defined as the proportion of malignant cells expressing the target antigen within the tumor—is a decisive factor for initial therapeutic efficacy. 81 Unlike hematologic malignancies, where targets such as CD19 and CD20 typically exhibit >90% coverage, solid tumors are characterized by profound spatial heterogeneity; thus, immunohistochemical results from a single biopsy often fail to accurately reflect the global expression landscape of the target antigen. 82 Clinical evidence suggests the existence of definitive efficacy thresholds in solid tumor therapies. For example, in Claudin18.2-targeted CAR-T cell therapy, durable clinical remission was predominantly observed in patient cohorts with a target coverage of ≥70% (immunohistochemical staining intensity of 2+/3+). 83 To address the clinical challenges posed by low antigen coverage, current research is focused on developing bispecific CARs to broaden the targeting spectrum and on strategies to induce the “bystander effect” and antigen spreading. 84 For instance, following CAR-T cell therapy targeting IL13Rα2, significant increases in inflammatory cytokines and endogenous immune cells within the cerebrospinal fluid were observed. This confirms that inflammatory signals released by CAR-T cells can remodel the TME and orchestrate broad, antigen-independent antitumor immunity. 73

The ultimate assurance of long-term efficacy lies in the stability of target expression under therapeutic pressure. Another fundamental cause for the translational failure of certain targets is their inability to circumvent antigen downregulation induced by immune selection pressure, leading to rapid tumor immune escape. 85 In one study, up to 71% of patients with recurrent glioblastoma exhibited target downregulation following anti-EGFRvIII CAR-T cell therapy; this mechanism is primarily attributed to the clonal selection of antigen-negative variants driven by intratumoral heterogeneity. 86 Conversely, optimal targets such as Claudin18.2 demonstrate exceptional antigen stability. Among patients treated with satri-cel, only 6% experienced antigen loss, and whole-body PET molecular imaging confirmed that the target lesions maintained robust tracer uptake posttreatment. 83 , 87 In summary, successful and optimal targets are characterized by a safe therapeutic window and highly stable expression profiles under therapeutic pressure. In contrast, targets that fail in clinical translation typically falter due to lethal on-target/off-tumor toxicities stemming from widespread, low-level basal expression or rapid antigen escape driven by high intratumoral heterogeneity.

To surmount these developmental bottlenecks, next-generation CAR-T engineering strategies are rapidly evolving. 88 For instance, the engineering of affinity-tuned CARs allows for the selective evasion of normal tissues with low antigen density, thereby mitigating on-target/off-tumor toxicity. Additionally, the design of Boolean logic-gated circuits (e.g., AND/NOT gates) leverages combinatorial antigen signatures to precisely restrict the spatial activation of T cells. 89 Furthermore, dual-targeting strategies (such as tandem CARs or pooled cell infusions), combined with rational combination regimens, are employed to systematically thwart antigen escape. Concurrently, the development of tunable “switch” systems (e.g., SUPRA Zipper adapter technology) enables the real-time modulation of CAR-T cell activity via exogenous small molecules. 90 Emerging in vivo CAR-T cell generation technologies are designed to simplify manufacturing processes and reduce costs. This approach bypasses the complexities of ex vivo expansion and the toxicities of lymphodepleting chemotherapy, offering a highly accessible paradigm capable of generating a robust, nonexhausted population of effector cells directly within the host. 91 , 92

Novel CAR design platforms are continuously overcoming the limitations of traditional antigen-dependent activation. By conferring CAR-T cells with autonomous activation capability independent of antigen stimulation, the CoupledCAR engineering platform achieved significant efficacy in a clinical trial for metastatic colorectal cancer (CRC), with an ORR of 57% and a median OS (mOS) of 26.1 months. 93 Beyond direct tumor targeting, neutralizing the immunosuppressive TME independently of tumor antigens represents another major breakthrough. Yagel et al. designed and constructed CAR-T cells targeting TREM2 + tumor-associated macrophages (TAMs), which achieve localized IL-12 secretion via synthetic biosensors. Preclinical models have demonstrated that this strategy effectively depletes immunosuppressive TAMs and enhances the infiltration of endogenous T and NK cells, inducing robust tumor regression without systemic toxicity. 94 To introduce spatiotemporal control, “EchoBack” CAR-T cells can be remotely activated by a focused ultrasound-controlled heat shock promoter. This sustains their attack on tumor cells for up to 5 days without significant exhaustion while allowing CAR molecules to degrade upon exiting the TME to avoid off-target damage. 95 Moreover, CRISPR-based gene regulation strategies have further enabled the tumor-directed delivery of cytokines such as IL-12 and IL-2, significantly enhancing the specificity, efficacy, and safety of CAR-T cell therapy within the TME through precise editing. 96 , 97

Combination therapy strategies further optimize efficacy. “Armored” CAR-T cells expressing factors such as IL-7 and CCL19 can recruit and activate endogenous immune cells. 98 The corresponding clinical trial ( NCT04405778 ) demonstrated a manageable safety profile and initial signs of efficacy in a first-in-human study for advanced solid tumors. 99 The combination of local treatment modalities with CAR-T cell therapy has also made significant progress. A phase Ib trial demonstrated that delivering anti-CEA CAR-T cells via hepatic artery infusion (HAI) followed by selective internal radiation therapy (SIRT) was safe and induced favorable biological responses in patients with CEA + liver metastases, avoiding severe CRS and neurotoxicity. 100 Moreover, by utilizing pressure-driven delivery technology, anti-CEA CAR-T cells successfully achieved lesion targeting and immune activation in a liver metastasis model, providing a new approach for overcoming the challenge of CAR-T cell infiltration in solid tumors. 101

In vivo CAR-T cell therapy

The traditional ex vivo cell therapy model faces a formidable industrialization gap. Its complex, personalized production process inevitably leads to high treatment costs and production bottlenecks, severely limiting clinical accessibility and large-scale industrial application. 102 , 103 To address this bottleneck, in vivo cell engineering has emerged. 104 – 106 Its core principle involves the intravenous injection of “off-the-shelf” delivery vehicles, such as engineered viral vectors or lipid nanoparticles (LNPs), to directly deliver the CAR gene to T cells or other immune cells within the patient, thereby achieving in situ reprogramming. 107 , 108 Therefore, it bypasses ex vivo manufacturing and avoids lymphodepleting chemotherapy, potentially unlocking the full potential of CAR technology. 109 , 110 This technology integrates cutting-edge advances from nanotechnology, RNA therapeutics, and virology, aiming to overcome the production limitations of traditional cell therapies and provide a more accessible solution for cancer immunotherapy. 110 – 112

Currently, the main technological pathways can be divided into two categories: those involving the integration of viral vectors and those involving nonintegrating RNA platforms. 113 , 114 Viral vector platforms achieve cell-specific transduction by engineering the envelope glycoproteins of lentiviruses or γ-retroviruses (e.g., with ligands targeting CD3 or CD8), integrating the CAR gene into the host genome to induce long-lasting antitumor immune responses. 115 , 116 INT2104, a CD7-targeting lentiviral vector developed by Interius BioTherapeutics, is the world’s first in vivo CAR-T cell therapy to enter human clinical trials ( NCT06539338 ). It achieves specific targeting and transduction of T cells and NK cells through the synergistic action of its engineered fusion protein and a CD7-binding agent. UB-VV111, derived from Umoja Biopharma’s VivoVec platform, has received FDA Investigational New Drug (IND) approval. It utilizes a surface-engineered envelope encoding a CD19-targeting CAR and a rapamycin-activated cytokine receptor (RACR) to enable the in vivo expansion of CAR-T cells. 117 Although viral platforms may induce durable responses, their potential risks of insertional mutagenesis and delayed-onset immunotoxicity require close monitoring.

In contrast, nonintegrating RNA platforms utilize LNPs to encapsulate CAR-encoding mRNA or circular RNA, achieving more precise delivery through natural tropism for immune cells or surface modification with targeting antibodies (e.g., anti-CD8 antibodies). 118 Since CAR expression is transient and nonintegrating, this platform offers a better theoretical safety profile and allows for therapeutic adjustment or maintenance of efficacy through repeated administration. CREATE Medicines (formerly Myeloid Therapeutics) leverages the natural tropism of LNPs for myeloid cells to develop CAR therapies targeting TROP2 and GPC3. Its drug candidates, MT-302 and MT-303, have entered phase I clinical trials for advanced solid tumors. Moreover, Capstan Therapeutics focuses on T cells. CellSeeker technology uses antibody-functionalized targeted LNPs (tLNPs) to specifically deliver CAR mRNA to CD8 + T cells, advancing the clinical translation of anti-CD19 CAR-T cell therapy. To fundamentally increase the efficiency of in vivo programming, Sanofi is engaged in the rational design of ionizable lipid molecules to optimize the transfection efficiency of LNPs for T cells. 119 However, this platform must address challenges such as hepatotoxicity, acute infusion reactions, and potentially insufficient efficacy due to transient expression. 120

The feasibility of this technological paradigm has received preliminary clinical validation. In July 2025, The Lancet reported the results of the first phase I clinical trial using BCMA-targeting in vivo CAR-T cell therapy (ESO-T01) for R/R MM. All four treated patients achieved clinical benefit (100% ORR), with no grade 4 or higher severe adverse events reported. 121 However, the efficiency of in vivo T cell transduction remains low (<10% in some LNP platforms), and the long-term safety of integrating viral vectors delivered systemically requires further evaluation in larger cohorts. Currently, in vivo engineering strategies for other immune cells, including NK cells, macrophages, and monocytes, are also under active exploration. 122 – 126

TCR-T cell therapy

TCR-T cell therapy is an important branch of ACT. It involves the introduction of tumor-specific TCR genes into a patient’s own T cells, enabling them to express TCRs capable of recognizing antigen peptides presented by major histocompatibility complex (MHC) molecules, thereby redirecting T cells to precisely kill tumor cells. 127 , 128 The foundational work in this field dates back to 1988, when Blüthmann et al. accomplished the first successful transfer of an exogenous TCR gene into normal T cells, equipping them with antigen-specific recognition capabilities and thereby pioneering a new era of TCR gene therapy. 129

Structure and function of TCR-T cells

At the molecular level, the TCR is a heterodimer composed of an α chain and a β chain linked by a disulfide bond, which noncovalently associates with the CD3 complex to form a functional receptor. 130 The ITAMs in the intracellular domains of CD3 initiate a phosphorylation cascade mediated by Src family kinases, activating ZAP-70 and PLCγ1, which subsequently promote T cell activation and cytotoxic molecule secretion via the NF-κB/MAPK signaling pathway. 131 , 132 This optimized signaling architecture, mediated by the kinetics of endogenous CD3ζ phosphorylation, endows TCR-T cells with exceptional antigen sensitivity, enabling activation thresholds as low as a single peptide-MHC (pMHC) complex (Fig. 4 ). 133 Unlike CAR-T cells, which primarily recognize cell surface antigens, TCR-T cells can identify antigenic peptides derived from the degradation of intracellular proteins and presented by MHC molecules, thereby targeting a broader antigen repertoire, including cancer-testis antigens (CTAs), tumor-specific neoantigens, and viral oncoproteins. 134 , 135 Fig. 4 The antitumor mechanism of TCR-T cells. The specific recognition of peptide-MHC complexes on-target cancer cells by the engineered TCR triggers TCR oligomerization and the phosphorylation of ITAMs by Lck, initiating a bifurcating intracellular signaling cascade. This cascade-mediated by ZAP-70, LAT, and downstream effectors—ultimately orchestrates the transcriptional activation of key genes responsible for T cell effector functions. Upon full activation, TCR-T cells execute their antitumor response through multiple coordinated mechanisms: releasing perforin and granzymes to directly mediate target cell lysis; secreting cytokines such as IL-2, IFN-γ, and TNF-α for immunomodulation; and expressing the death receptor ligand FasL to induce tumor cell apoptosis. AP1 activator protein 1, APCs antigen-presenting cells, DAG diacylglycerol, FasL Fas ligand, Grb2 growth factor receptor-bound protein 2, HSP27 heat shock protein 27, IFN-γ interferon-gamma, IL-2 interleukin-2, IP 3 inositol 1,4,5-trisphosphate, ITAM immunoreceptor tyrosine-based activation motif, LAT linker for activation of T cells, Lck lymphocyte-specific protein tyrosine kinase, MAPK mitogen-activated protein kinase, MHC major histocompatibility complex, NFAT nuclear factor of activated T cells, PI(4,5)P 2 phosphatidylinositol 4,5-bisphosphate, PKCs protein kinase C family, PLCγ1 phospholipase C gamma 1, RAS Rat sarcoma virus oncogene homolog, RASGRP1 RAS guanyl-releasing protein 1, SOS Son of Sevenless, TNF-α tumor necrosis factor-alpha, ZAP-70 Zeta-chain-associated protein kinase 70. Created with BioRender.com

Furthermore, compared to the disorganized and transient nonclassical synapses formed by CAR-T cells, the immunological synapse (IS) formed between TCR-T cells and target cells is highly structured and temporally stable. This structural stability confers distinct mechanistic advantages upon TCR-T cells in overcoming the formidable barriers of solid tumors, specifically antigen heterogeneity and the immunosuppressive TME. 136 First, the classical TCR IS—organized into well-defined supramolecular activation clusters (SMACs)—enables exquisite antigen sensitivity through sustained serial triggering. Because a stable IS allows a TCR-T cell to be triggered by as few as 1–10 pMHC complexes, TCR-T cells can effectively recognize and eradicate tumor variants with profoundly downregulated antigen expression, directly counteracting tumor heterogeneity and minimizing the risk of antigen escape. 137 Second, regarding the TME, the physiological signaling orchestrated by a stable IS intrinsically protects T cells from the tonic signaling and rapid functional exhaustion frequently observed in CAR-T therapies. 138 Moreover, this stable focal adhesion facilitates the highly polarized and directional exocytosis of perforin and granzymes. 139 This concentrated delivery maximizes cytotoxic efficiency against target cells while sparing surrounding immune effectors, thereby preserving the viability and serial killing capacity of TCR-T cells even within the harsh, immunosuppressive TME of solid tumors.

Application of TCR-T cell therapy in cancer treatment

The clinical translation of TCR-T cell therapy began in 1999 when Clay et al. first demonstrated in a clinical study that T lymphocytes modified with an exogenous TCR gene exhibited specific antitumor activity in melanoma patients. 140 In 2006, a clinical trial conducted by Rosenberg’s team further validated its feasibility. Objective tumor regression was observed in 2 out of 17 melanoma patients, providing the first clinical-level demonstration of the potential of genetically engineered TCRs for cancer treatment. 141 Subsequent research utilized directed evolution platforms such as yeast display and phage display to engineer TCR affinity maturation, significantly enhancing the strength and specificity of TCR-pMHC interactions. 142 Moreover, the precise selection of T cell subsets with the potential for long-term persistence and potent killing, such as central memory T cells, as substrates for genetic modification ensured the long-term survival and functional maintenance of the infused cells in vivo. 143 In 2022, the FDA approved the first TCR-based therapeutic, tebentafusp, which targets gp100, for the treatment of HLA-A*02:01-positive unresectable or metastatic uveal melanoma (Table 3 ). Although tebentafusp is a soluble bispecific fusion protein rather than a living cell therapy, its pivotal phase III study revealed that, compared to standard therapy, tebentafusp reduced the risk of death by 49% and increased the one-year OS rate to 73.2%, indicating the official entry of TCR-targeted immune modalities into a new stage of clinical practice. 144 Table 3 Approved TCR-T, TIL, and DC therapies for cancer Product name (INN, Brand) Type Key status Target Developer/Sponsor Approved regions First approval Approved indication(s) Afamitresgene autoleucel (Tecelra) TCR-T First FDA-approved TCR-T therapy for solid tumors MAGE-A4 Adaptimmune USA 2024-08-02 Advanced synovial sarcoma Lifileucel (Amtagvi) TIL First FDA-approved TIL therapy Tumor neoantigens Iovance Biotherapeutics USA 2024-02-16 Advanced melanoma Hybricell Hybrid cell vaccine – Not specified Genoa Biotecnologia BR 2004-01-01 Advanced melanoma, RCC CreaVax-RCC DC vaccine First approved autologous DC therapy in KR Not specified JW CreaGene KR 2007-01-01 mRCC Sipuleucel-T (Provenge) DC vaccine First FDA-approved therapeutic cancer vaccine and autologous cell immunotherapy PAP Dendreon USA 2010-04-29 Hormone-refractory prostate cancer APCEDEN DC vaccine – Not specified APAC Biotech IN 2017-04-05 Prostate cancer, ovarian cancer, CRC, NSCLC BR Brazil, CRC colorectal cancer, FDA Food and Drug Administration, IN India, INN International Nonproprietary Name, KR South Korea, MAGE-A4 melanoma-associated antigen 4, mRCC metastatic renal cell carcinoma, NSCLC non-small cell lung cancer, PAP prostatic acid phosphatase, RCC renal cell carcinoma

In the field of hematologic malignancies, the clinical exploration of TCR-T cell therapy has focused primarily on targets such as WT1 and PRAME (Table 4 ). 145 , 146 WT1, a TAA overexpressed in AML and myelodysplastic syndrome (MDS), has shown favorable safety in early clinical trials of specific TCR-T cell therapy, with some patients achieving a reduced leukemic cell burden in the bone marrow and clearance of minimal residual disease (MRD). 147 , 148 A clinical trial reported a 40% ORR in AML patients treated with WT1-specific TCR-T cells, including a durable CR, and the efficacy was correlated with the magnitude of engineered T cell expansion in vivo. 149 In another trial targeting an HLA-A*02:01-restricted WT1 epitope, after the infusion of autologous TCR-T cells in 8 high-risk patients, 5 had detectable engineered T cells persisting for over one year, and these cells retained specific immunoreactivity to the WT1 antigen peptide in vitro. 147 Furthermore, PRAME, a representative CTA, is heterogeneously expressed in myeloid and lymphoid malignancies. Preclinical investigations have demonstrated that PRAME-specific TCR-T cells can effectively recognize and eliminate leukemic blasts. Currently, PRAME-targeting TCR-T cell therapies (such as MDG1011) are being evaluated in clinical trials to assess their safety profile and antitumor activity. Table 4 Key clinical trials of TCR-T and TIL therapies for cancer Type Target NCT number/Registry Cancer type Phase Enrollment ( n ) Key outcomes Ref. TCR-T PRAME NCT03686124 R/R melanoma and sarcoma I/II 40 Cohort 1a: ORR 48.1%, mPFS 2.8 mo, mOS 7.5 mo; Cohort 1b: ORR 61.5%, mDoR 8.1 mo, mPFS 5.7 mo, mOS NR 155 TCR-T WT1 NCT01640301 AML I/II 100 (TCR-T: 12; Control: 88) TCR-T: RFS 100.0%, OS 100.0% (44-mo follow-up); Control: 3-yr RFS 54.0%, OS 60.0% 149 TCR-T NY-ESO-1 NCT04318964 Advanced soft tissue sarcoma I 12 ORR 41.7%; DCR 83.3%; mTTR 1.9 mo; mDoR 13.1 mo; mPFS 7.2 mo 152 TCR-T MAGE-A4 NCT04044768 Advanced/metastatic SS or MRCLS II 52 (SS: 44; MRCLS: 8) ORR 36.6% (SS: 38.6%; MRCLS: 25.0%) at median follow-up of 32.6 mo 154 TIL Tumor neoantigens NCT02278887 Metastatic melanoma III 168 TIL vs. Ipilimumab: mPFS 7.2 mo vs. 3.1 mo, ORR 48.8% vs. 21.4%, mOS 25.8 mo vs. 18.9 mo 496 TIL Tumor neoantigens NCT03215810 NSCLC I 20 Confirmed response: 2 CR (≥1.5 yr), 1 PR; Median tumor reduction: 35.5% 497 TIL Tumor neoantigens – Metastatic melanoma I 93 ORR 55.9%; CR 21.5%; 3-yr OS in CR patients: 100.0% 178 TIL Tumor neoantigens NCT02360579 Metastatic melanoma II 66 ORR 36.4%; DCR 80.3%; mOS 17.4 mo 498 AML acute myeloid leukemia, CR complete response, DCR disease control rate, MAGE-A4 melanoma-associated antigen 4, mDoR median duration of response, mOS median overall survival, mPFS median progression-free survival, MRCLS myxoid/round cell liposarcoma, mTTR median time to response, NR not reached, NSCLC non-small cell lung cancer, NY-ESO-1 New York esophageal squamous cell carcinoma 1, ORR objective response rate, OS overall survival, PR partial response, PRAME preferentially expressed antigen in melanoma, R/R relapsed/refractory, RFS relapse-free survival, SS synovial sarcoma, WT1 Wilms tumor 1

For solid malignancies, TCR-T cell therapy has demonstrated remarkable prospects, with CTAs emerging as the premier target category. They are abundantly expressed in various solid tumors but transcriptionally silenced in normal adult somatic tissues (excluding immune-privileged germ cells). This differential expression establishes an exceptionally wide therapeutic window. NY-ESO-1 has historically been the most extensively targeted CTA in TCR-T trials due to its robust immunogenicity and its dense and homogeneous expression in specific malignancies. An early pilot trial reported an ORR of 67% (4/6) in synovial sarcoma, with durable responses exceeding one year in some melanoma patients, providing initial confirmation of its antitumor activity. 150 Subsequent extended follow-up further confirmed the durability of the efficacy. In the synovial sarcoma cohort, the ORR was maintained at 61%, with a 3-year survival rate of 38%; the melanoma patient cohort achieved an ORR of 55%, demonstrating stable disease (SD) control capability. 151 An optimized, affinity-matured generation of TCR constructs demonstrated an ORR of 41.7% and a DCR of 83.3% in a phase I evaluation of advanced synovial sarcoma, with no major safety concerns observed. 152 Another widely recognized CTA is MAGE-A4, an ideal target broadly expressed across multiple solid tumors yet virtually absent in normal tissues, thereby serving as a promising candidate for precision tumor eradication. In August 2024, the TCR-T cell therapy afamitresgene autoleucel, which targets this antigen, received FDA approval for treating synovial sarcoma, making it the world’s first approved engineered TCR-T cell therapy. 153 The pivotal phase II trial (SPEARHEAD-1) demonstrated an independently assessed ORR of 37% at a median follow-up of 32.6 months, which was significantly superior to that of historical controls. 154

Furthermore, the PRAME-targeting TCR-T cell therapy IMA203 has also demonstrated excellent performance in PRAME-positive solid tumors. Initial results from a first-in-human phase I trial involving HLA-A*02:01-positive patients established a manageable safety profile and yielded a confirmed/unconfirmed ORR (c/uORR) of 52.5% across 40 evaluable patients. Notably, in the phase Ib high-dose cohort, the cORR further increased to 54.5%, with the melanoma subgroup demonstrating a 50% response rate and durable efficacy exceeding 12 months, highlighting the application value of the CTA target class. 155 Viral-associated antigens and differentiation antigens are also important areas where breakthroughs in TCR-T cell therapy have been made. TCR-T cell therapy targeting the HPV-16 E7 oncoprotein achieved an ORR of 50% in patients with PD-1 inhibitor-resistant metastatic cervical cancer. 156 The combination of TCR-T cell therapy targeting the latent EBV membrane protein LMP2 with a PD-1 inhibitor resulted in a 33.3% partial response (PR) rate and a 50% DCR in patients with advanced nasopharyngeal carcinoma. 157 TCR-T cell therapy targeting personalized neoantigens has also achieved preliminary success. These therapies target neoantigens derived from somatic mutations, providing superior tumor specificity and a favorable safety margin. 158 For instance, TCR-T cell therapy targeting the KRAS G12D neoantigen achieved 72% overall tumor regression (PR) in a patient with metastatic pancreatic cancer, with rapid shrinkage of pulmonary metastases evident within one month postinfusion, highlighting its exceptional specificity and potency. 159 Another study reported by Parkhurst et al. revealed that personalized neoantigen-reactive TCR-T cell therapy administered to patients with metastatic CRC exhibited good safety and preliminary antitumor activity, with tumor shrinkage lasting 4–7 months in 43% of patients. 160

However, similar to CAR-T cell therapy, the field faces challenges, including an immunosuppressive TME, physical barriers in solid tumors, and antigen escape. Additionally, there is a unique risk of TCR mispairing, potentially leading to autoimmune reactions. 161 Therefore, current research focuses on optimizing in vitro culture to obtain youthful T cells, using gene editing to knock out endogenous TCRs, establishing high-throughput TCR screening and neoantigen identification platforms, and exploring combination strategies with immune checkpoint inhibitors (ICIs) or oncolytic viruses.

TIL therapy

TIL therapy represents a pivotal strategy in cancer treatment, the biological basis of which is the natural selection of T cell clones by the TME in situ. 162 Unlike strategies that confer specificity through genetic engineering, such as CAR-T and TCR-T cell therapies, TIL therapy directly utilizes the endogenous lymphocyte repertoire present within the tumor mass, which primarily consists of CD8 + cytotoxic T cells and CD4 + helper T cells, with a potential minor component of NK cells. 163 The reinfusion of these cells after large-scale ex vivo expansion driven by cytokines such as IL-2 essentially represents functional amplification of the polyclonal TCR repertoire enriched under “in situ antigen selection pressure” within the tumor, with the goal of restoring sufficient numbers and effector functions to tumor-reactive T cell clones to overcome suppression by the TME. 164 , 165

Technical process and core advantages

Since Rosenberg and colleagues first reported in 1988 the application of autologous TILs combined with high-dose IL-2 for treating metastatic melanoma to achieve tumor regression, the key technical aspects of TIL therapy have been progressively established. 166 , 167 The standard procedures include surgical resection of tumor tissue and TIL isolation, microwell culture, and rapid expansion in IL-2-containing medium to enrich reactive clones, the use of lymphodepleting chemotherapy agents (such as cyclophosphamide and fludarabine) prior to infusion, and postinfusion IL-2 support therapy to promote T cell survival and expansion in vivo. 168 , 169 The core advantage of TIL therapy lies in the broad antigen recognition capacity afforded by its polyclonal TCR repertoire. This repertoire enables the targeting of not only differentiation antigens and CTAs but also tumor-specific neoantigens via specific CD8 + T cell clones, facilitating the specific killing of tumor cells. 170 Studies have demonstrated that the presence of neoantigen-reactive T cell clones is significantly associated with durable clinical responses in patients with various epithelial cancers, such as breast cancer and CRC, following TIL therapy. 171 , 172 This multitarget recognition capability gives TIL therapy a natural advantage over single-antigen-targeting CAR-T or TCR-T cell therapies in addressing the high heterogeneity of solid tumors, effectively reducing the risk of tumor immune escape due to antigen loss or mutation. 173 , 174

Application of TIL therapy in cancer treatment

The most mature and evidence-supported indication for TIL therapy primarily comes from solid tumors, particularly advanced melanoma (Table 4 ). 175 , 176 A systematic evaluation and meta-analysis of 13 clinical studies by Dafni et al. confirmed the sustained efficacy of TIL combined with IL-2 in patients with advanced cutaneous melanoma, with a pooled ORR of 41% and a CRR of 12%. Subgroup analysis indicated superior outcomes for the high-dose IL-2 regimen, with an ORR of 43% and a CRR of 14%, compared to an ORR of 35% and a CRR of 7% in the low-dose IL-2 cohort. The study also revealed that among patients who achieved a CR in the high-dose IL-2 group, the vast majority maintained their response during a median follow-up of 40 months after remission, demonstrating the durability of the clinical benefit. 177 In another large phase II study, 93 melanoma patients treated with TIL therapy achieved an ORR of 56% and a CRR of 22%. 178 In February 2024, the FDA granted accelerated approval to the world’s first TIL therapeutic product, lifileucel (Amtagvi), for the treatment of PD-1-resistant advanced melanoma. Its pivotal study revealed an ORR of 31.5% and a CRR of 4.5% in a heavily pretreated patient population, further establishing the important role of TILs in solid tumor treatment. 179

In the field of HPV-associated cervical cancer, TIL therapy has also demonstrated significant therapeutic potential. Studies have shown that the reinfusion of HPV-specific TILs isolated and expanded from patient tumor tissue can induce a CR in some patients and significantly prolong survival. 180 Exploratory studies in PD-1-resistant NSCLC have also suggested the safety and preliminary efficacy of TIL therapy. 181 , 182 For digestive system tumors, a recent clinical trial in patients with MMR-proficient (MMRp) metastatic gastrointestinal cancer demonstrated that neoantigen-reactive TIL therapy yielded an ORR of 7.7% as monotherapy, increasing to 23.5% when combined with the anti-PD-1 antibody pembrolizumab. 183 Our team recently reported two cases of advanced HCC patients who received autologous TIL infusion combined with a PD-1 inhibitor after palliative cytoreductive hepatectomy, resulting in complete resolution of pulmonary metastases and long-term tumor-free survival. These results suggest the potential for a curative outcome with this combination strategy in a subset of advanced HCC patients. 184

With respect to safety, the toxicity profile of TIL therapy is primarily associated with the concomitant high-dose IL-2 infusion in the regimen. Common adverse events include fever, chills, and capillary leak syndrome, which can usually be managed with supportive care. 185 Compared to CAR-T cell therapy, the incidence of associated CRS and ICANS is lower. Furthermore, as TILs constitute a polyclonal T cell population, the TCR repertoire formed through negative selection in the thymus reduces the risk of autoimmunity. Consequently, their overall safety profile is superior to that of high-affinity engineered T cell products targeting a single antigen. 185

In contrast, evidence for TIL application in hematologic malignancies remains limited. This is primarily due to the lack of accessible solid tumor masses for TIL preparation in hematologic malignancies, coupled with significant differences in their antigen-presenting microenvironments compared to those of solid tumors. Consequently, current clinical research continues to focus predominantly on solid tumors.

Despite its potential in oncology, TIL therapy is confronted with several significant challenges. Differences in immunogenicity among solid tumors mean that not all tumor types can reliably yield highly reactive TILs, and the personalized manufacturing process introduces challenges in batch-to-batch variation and quality consistency. 186 Additionally, the immunosuppressive TME and mismatched chemokine axes limit the homing and persistence of reinfused cells. 187 To overcome these bottlenecks, current research focuses on the neoantigen-directed selection of individualized T cell clones, precise gene editing of key exhaustion pathways, and the acceleration and standardization of manufacturing processes. 187 By optimizing lymphodepleting chemotherapy and IL-2 support strategies and exploring combination regimens with ICIs, targeted therapies, and radiotherapy, TIL therapy is expected to play a therapeutic role in more tumor types and earlier lines of treatment, offering new options for advanced cancer patients.

γδ T cell therapy

γδ T cells constitute a unique subset of T lymphocytes, accounting for only 1–5% of peripheral T cells, but display remarkable immunological features that distinguish them from the major αβ T cell subset. 188 , 189 Their most prominent advantage lies in MHC-independent antigen recognition, enabling them to directly sense stress-induced ligands on tumor cell surfaces, such as MICA/B, phosphoantigens (pAgs), and BTN3A1, and rapidly mediate cytokine release and cytotoxic killing. 190 , 191 Notably, γδ T cells possess a dual recognition system: they not only recognize antigens through their γδ TCR specificity but also express natural cytotoxicity receptors such as NKG2D and DNAM-1, enabling them to simultaneously respond to stress signals within the TME. 192 , 193 This synergistic mechanism significantly reduces the risk of antigen escape—when tumor cells downregulate the expression of TCR-targeted antigens, they often simultaneously upregulate the expression of NKG2D ligands, allowing γδ T cells to still kill tumor cells via the innate immune pathway. 194 , 195 Moreover, compared to αβ T cells, the MHC-independent activation of γδ T cells results in a substantially lower risk of graft-versus-host disease (GvHD) in allogeneic settings, a key safety advantage underpinning their development as “off-the-shelf” cellular products. 196 In recent years, γδ T cell therapy has progressed from basic research to clinical exploration, including infusions of ex vivo-expanded autologous γδ T cells, CAR-γδ T cell engineering, and bispecific antibody (bsAb)-guided strategies, demonstrating preliminary efficacy and a favorable safety profile in hematologic malignancies and solid tumors, including liver and lung cancers. 197 – 199

Adoptive transfer of γδ T cells

The adoptive transfer of ex vivo-expanded autologous or allogeneic γδ T cells is the earliest strategy explored clinically in this field. 200 In 2003, the first γδ T cell clinical trial was officially registered on ClinicalTrials.gov . That same year, Wilhelm et al. systematically reported for the first time the clinical outcomes of using expanded γδ T cells to treat R/R lymphoma, providing the first human data supporting the antitumor activity of γδ T cells. 201 As of November 12, 2025, a total of 49 clinical trials related to γδ T cells have been registered, primarily focused on evaluating the safety and preliminary efficacy of Vγ9Vδ2 T cells in treating cancer. Vγ9Vδ2 T cells, as the primary effector subset, can be stimulated by aminobisphosphonate drugs such as zoledronate, which induce the intracellular accumulation of phosphoantigens in target cells, thereby enabling large-scale γδ T cell expansion when combined with IL-2/IL-15. 202

In hematologic malignancies, allogeneic Vγ9Vδ2 T cell infusion has shown good safety with no risk of GvHD in the treatment of leukemia after hematopoietic stem cell (HSC) transplantation, and long-term patient survival is positively correlated with the degree of γδ T cell reconstitution. 203 In solid tumors, phase I clinical trials have indicated that multiple infusions of expanded Vγ9Vδ2 T cells can significantly prolong the mOS of patients with advanced liver cancer and lung cancer. 204 Notably, tissue-resident Vδ1 T cells are significantly enriched in liver metastases of CRC, and their infiltration density is closely associated with improved patient OS. 205 Using the “Delta One T” (DOT) expansion protocol, Vδ1 T cells can achieve a thousand-fold expansion and demonstrate significant antitumor activity in patient-derived xenograft models of AML. 206 , 207

CAR-γδ T cell therapy

With the development of genetic engineering technology, the use of CAR-γδ T cells has emerged as a new generation of therapeutic strategies. CAR-γδ T cells combine the inherent MHC-unrestricted killing advantage of γδ T cells with the high targeting specificity of CAR structures, demonstrating excellent potential in preclinical and early clinical studies. 208 The world’s first clinical study of CAR-γδ T cell therapy began in 2017, with the aim of evaluating the safety and treatment feasibility of autologous CD19-targeting CAR-γδ T cell therapy in patients with R/R B-cell malignancies. Since then, the number of related clinical trial registrations has increased significantly, with the scope expanding from hematologic malignancies to various solid tumors, such as liver cancer and pancreatic cancer, and targeting antigens, including CD15, CD20, CD123, GPC3, and prostate stem cell antigen (PSCA). 209 , 210 The CD20-targeting CAR-γδ T cell product (ADI-001) developed by Adicet Bio has shown significant efficacy in a phase I trial ( NCT04735471 ) for B-cell lymphoma. Even in patients who had progressed after receiving prior CAR-T cell therapy, this treatment could still induce objective responses, and the incidence of severe CRS was significantly lower than that with CAR-T cell therapy. 211

With respect to solid tumors, GPC3-specific CAR-Vδ1 T cells (ADI-002) demonstrated high-efficiency tumor clearance in liver cancer xenograft models. A construct incorporating secretory IL-15 (sIL-15) (GPC3.CAR/sIL-15) enhanced T cell proliferation and persistence, achieving complete tumor regression without GvHD. 212 Anti-CD70 CAR-Vδ1 T cell therapy (ADI-270) for clear cell RCC (ccRCC) employs a unique design based on the CD27 receptor. Preclinical studies have confirmed its ability to efficiently clear CD70-positive tumor cells (including low-expression subsets), reverse the immunosuppressive microenvironment via a dominant-negative TGFβRII, and reduce the risk of host T cell rejection. 213 Currently, the first-in-human trial for this therapy has been initiated in R/R ccRCC ( NCT06480565 ). In ovarian cancer treatment, Vγ9Vδ2 T cells expressing an NKG2D-CAR, by targeting stress ligands such as MICA/B, extended median mouse survival by 132% in a xenograft model. 214 A related clinical trial ( NCT05302037 ) is currently underway to validate the efficacy of this approach.

Antibody-mediated activation and bispecific engager strategies

Antibody-based strategies provide an “off-the-shelf” alternative for precisely activating endogenous γδ T cells. 215 The anti-BTN3A1 monoclonal antibody ICT01 activates Vγ9Vδ2 T cells by mimicking the effect of phosphoantigens. 216 Early-phase clinical evaluations have demonstrated that ICT01 monotherapy is well tolerated and exhibits preliminary antitumor activity across R/R hematologic malignancies without inducing severe CRS. 217 Bispecific antibodies (bsAbs), via their unique bivalent structure, simultaneously and specifically bind to receptors on γδ T cells and TAAs, directly bridging effector and target cells in vivo and thereby directionally activating the cytotoxic function of γδ T cells without the need for ex vivo expansion. 218 LAVA-1207, a bsAb targeting prostate-specific membrane antigen (PSMA) and the Vγ9Vδ2 TCR developed by Lava Therapeutics, showed no DLT at the 40 μg dose in an early clinical study for metastatic castration-resistant prostate cancer (mCRPC), with 3 out of 8 evaluable patients achieving SD. 219 Compared to traditional CD3-targeting bsAbs, γδ bispecific T cell engagers (bsTCEs) have significant advantages. 220 They specifically target the γδ T cell subset, which helps to prevent the activation of immunosuppressive regulatory T cells (Tregs), thereby reducing the risk of immune-related toxicity. Research has indicated that the cytokine release induced by γδ bsTCEs is significantly lower than that induced by traditional CD3 bsTCEs and that they do not result in severe CRS. 221

Interestingly, the unique tumor-sensing capabilities of γδ TCRs are also being leveraged to redirect conventional αβ T cells. An innovative paradigm involves the development of γδ TCR anti-CD3 bispecific molecules (GABs). Unlike traditional bsTCEs that aim to recruit endogenous γδ T cells, GABs fuse the soluble extracellular domains of tumor-reactive γδ TCRs with a CD3-binding moiety. This design utilizes the γδ TCR as a targeting module to recognize metabolic alterations (e.g., phosphoantigen accumulation) in tumor cells, while the anti-CD3 domain robustly activates abundant circulating αβ T cells. Preclinical evaluations have demonstrated that GABs successfully bridge metabolic tumor targeting with potent αβ T cell-mediated cytotoxicity, representing a novel extension of γδ T cell biology into the field of soluble engagers. 222

However, the low frequency of γδ T cells in peripheral blood and the inefficient expansion of key effector subsets such as Vδ1 cells make large-scale production extremely challenging, necessitating further optimization of cytokine combinations and novel artificial antigen-presenting technologies. 223 , 224 Immunosuppression within the TME is a common obstacle for cell therapies. Compared with αβ T cells, γδ T cells are particularly sensitive to immunosuppressive factors in the TME, such as TGF-β and adenosine, making them prone to functional exhaustion. Using gene editing technologies such as CRISPR/Cas9 to precisely knock out the TGFβRII gene in γδ T cells can enable them to maintain antitumor function in TGF-β-rich microenvironments. 225 Furthermore, αPD-L1-γδ T cells, generated by anchoring anti-PD-L1 nanobodies via metabolic glycan labeling and click chemistry, can not only specifically target PD-L1-high tumors but also recruit endogenous CD8 + T cells via the CCL5/CCR5 axis, synergistically reversing the immunosuppressive microenvironment. 215 At the level of personalized medicine, γδ T cell therapy, guided by single-cell sequencing for receptor repertoire analysis, exhibits greater adaptability to antigenic diversity than conventional CAR-T cell therapy, facilitating more precise and customized therapies.

NK cell therapy

NK cells, as the effector population of innate lymphoid cells (ILCs), have broad prospects in cancer treatment because of their unique advantages of not requiring antigen pre-sensitization, being MHC-unrestricted, and having a low risk of GvHD. 226 , 227 Their killing mechanism relies primarily on the formation of an immunological synapse, inducing target cell membrane perforation and apoptosis via the directed release of perforin and granzymes while also activating the caspase cascade through the FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways. 228 , 229 Furthermore, cytokines secreted by NK cells, such as IFN-γ and TNF, can not only inhibit tumor proliferation and disrupt angiogenesis but also recruit antigen-presenting cells (APCs), such as cDC1s, by producing chemokines such as XCL1 and CCL3/4/5, thereby effectively bridging and initiating adaptive immune responses. 230 , 231 Notably, CD16a (FcγRIIIa) expressed on the NK cell surface can mediate antibody-dependent cellular cytotoxicity (ADCC) by recognizing the Fc portion of therapeutic antibodies (e.g., rituximab and trastuzumab) bound to tumor cells, efficiently clearing antibody-opsonized targets. 232 – 234 In recent years, engineered modification strategies such as CAR-NK cells have further enhanced the potential of NK cells for targeted tumor therapy. 235 Currently, the main strategies for NK cell-based cancer therapy include adoptive NK cell infusion from autologous or allogeneic sources and genetically engineered, targeted CAR-NK cell therapy. 236

Adoptive transfer of NK cells

Autologous NK cell therapy, which involves extracting, expanding ex vivo, and reinfusing the patient’s own NK cells, effectively avoids the risk of immune rejection, but its efficacy is often limited by the functionally suppressed state of NK cells in cancer patients. 237 , 238 In contrast, allogeneic NK cell therapy utilizes NK cells derived from healthy donors. This approach not only overcomes functional defects in the patient’s own cells but also significantly enhances recognition and killing activity against tumor cells through the KIR–ligand mismatch mechanism (Fig. 5a ). 239 Fig. 5 Mechanisms of NK and NKT cell-based cancer immunotherapy. a NK cells eliminate tumors via natural cytotoxicity, CD16-mediated antibody-dependent cellular cytotoxicity, and proinflammatory cytokine secretion. b CAR engineering confers tumor-specific recognition and enhances targeted killing by NK cells. c iNKT cells orchestrate broad antitumor responses through direct CD1d-restricted cytotoxicity and indirect immunomodulation via DC licensing and immune cell activation. Furthermore, CAR modification optimizes their targeting precision. α-GalCer α-galactosylceramide, FasL Fas ligand, Fc fragment crystallizable, iTCR invariant T cell receptor, KIR killer cell immunoglobulin-like receptor, NKG2D natural killer group 2D, TNF-α tumor necrosis factor-alpha, TRAIL tumor necrosis factor-related apoptosis-inducing ligand. Created with BioRender.com

In hematologic malignancies, allogeneic NK cell infusion has demonstrated the capacity to induce durable antitumor responses. A systematic review encompassing 402 AML patients revealed a CRR of 48.22%, alongside a manageable adverse effect profile. 240 In the treatment of B-cell lymphoma and CLL, a therapeutic regimen utilizing haploidentical NK cells combined with rituximab and IL-2 yielded an ORR of 27%. 241 Furthermore, in patients with refractory MM, allogeneic NK cell infusion following intensive myeloablative conditioning induced near-CRs in approximately half of the cohort, highlighting its distinct potential for disease control within the transplant context. 242 The application of novel engager technologies has further enhanced therapeutic precision. For instance, SAR443579, a trifunctional NKp46×CD16a engager targeting CD123, demonstrated a composite CRR (CR + CRi) of 12% in a phase I/II clinical trial involving 43 patients with R/R AML, with no DLTs or neurotoxicity events observed in the highest dose group. 243 Moreover, the tetravalent bsAb AFM13 (targeting CD30 and CD16a) has been utilized to redirect cytokine-induced memory-like (CIML) NK cells. A phase I clinical study revealed that AFM13-mediated immunological synapse formation significantly upregulated the transcription of inflammatory pathway genes, thereby sustaining the in vivo activation of NK cells for over three weeks. 244 In patients with heavily pretreated, refractory CD30 + lymphomas, this bispecific-“armed” NK cell therapy achieved an exceptional ORR of 92.9% and a CRR of 66.7%, notably without inducing CRS or GvHD. These outcomes provide compelling validation for the profound efficacy and superior safety profile of “off-the-shelf” allogeneic NK cell composite therapies.

With respect to solid tumors, patients with HCC who received local high-dose autologous NK cells combined with hepatic arterial infusion chemotherapy achieved an ORR of 63.6%, a DCR of 81.8%, an mPFS of 10.3 months, and an mOS of 41.6 months, representing a significant survival extension (Table 5 ). 245 In May 2025, allogeneic NK cell therapy derived from peripheral blood mononuclear cells (PBMCs) developed in China received Orphan Drug Designation from the FDA, marking an important milestone for NK cell therapy in the field of liver cancer treatment. In NSCLC, a therapeutic regimen employing autologous NK cells combined with pembrolizumab increased the 2-year OS rate to 58.3% in patients whose first-line platinum-based therapy failed, which was significantly superior to the 16.7% rate in the monotherapy group. 246 Notably, under this treatment regimen, patients with EGFR-mutant advanced lung adenocarcinoma achieved an ORR of 75% and an mPFS of 9 months. Furthermore, clinical exploration of NK cell therapy for solid tumors such as neuroblastoma, HER2-positive breast cancer, CRC, and advanced GC has demonstrated its potential value in inducing disease remission, stabilizing conditions, and prolonging disease-free survival. 247 , 248 Table 5 Key clinical trials of cell therapies beyond T cells Type Target NCT number/Registry Cancer type Phase Enrollment ( n ) Key outcomes Ref. NK Multitarget KCT0003973 Advanced HCC I 11 ORR: 63.6% (CR: 36.4%; PR: 27.3%); DCR: 81.8%; mPFS: 10.3 mo; mOS: 41.6 mo 245 NK Multitarget NCT03662477 NSCLC I 48 RR: 75.0% (with NK) vs. 16.7% (without NK); mPFS: 9.0 vs. 6.0 mo 246 CAR-NK CD123 NCT05086315 R/R AML/ALL I/II 23 CRR (1000 μg/kg dose cohort): 37.5%; Composite CR (CR + CRi): 12.0% 243 CAR-NK CD19 NCT05472558 R/R LBCL I 8 ORR: 62.5%; CR: 50.0%; mPFS: 9.5 mo 258 CAR-NK CD33 NCT05008575 R/R AML I 10 60.0% MRD-negative CR by Day 28; No ICANS, GvHD, or Grade 3–4 AEs (except manageable cytopenia) 259 CAR-NK HER2 NCT03383978 GBM I 9 5 SD (duration 7–37 wk); No DLT or CRS observed 264 CAR-NK CD19 NCT03056339 B-cell malignancies I/II 37 ORR: 48.6% (Day 30/100); CR: 27.0% (Day 30), 29.7% (Day 100); 1-yr OS: 68.0%; 1-yr PFS: 32.0%; No CRS, ICANS, or GvHD reported 252 CAR-M HER2 NCT04660929 HER2 + metastatic solid tumors I 14 BOR (SD): 28.6%; Target lesion reduction: 40.7%; ctDNA reduction: 61.5%; mPFS: 1.5 mo; No DLT or Grade ≥3 CRS/ICANS 297 CAR-NKT GD2 NCT03294954 Neuroblastoma I 12 ORR: 25.0% (2 PR, 1 CR); 1 CR sustained for 12 mo without further therapy; No DLTs; 1 Grade 2 CRS 499 DC TAAs NCT02993315 Stage IIIB/C melanoma III 148 2-yr RFS: 36.8% (DC vaccine) vs. 46.9% (control); mRFS: 12.7 vs. 19.9 mo; Immunological response: 67.1% vs. 3.8% 363 DC TAAs NCT00045968 GBM III 331 mOS: 19.3 mo (vs. 16.5 mo control); 48/60-mo OS: 15.7%/13.0% vs. 9.9%/5.7% 364 DC TAAs NCT00065442 mCRPC III 512 Reduced death risk by 22.0%; mOS: 25.8 mo; 36-mo survival: 31.7%; Common AEs: chills, fever, headache 360 AE adverse event, ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, BOR best overall response, CR complete response, CRi complete response with incomplete hematologic recovery, CRR complete response rate, CRS cytokine release syndrome, ctDNA circulating tumor DNA, DCR disease control rate, DLT dose-limiting toxicity, GBM glioblastoma, GD2 disialoganglioside 2, GvHD graft-versus-host disease, HCC hepatocellular carcinoma, HER2 human epidermal growth factor receptor 2, ICANS immune effector cell-associated neurotoxicity syndrome, KCT Korean Clinical Trial Registry, LBCL large B-cell lymphoma, mCRPC metastatic castration-resistant prostate cancer, mOS median overall survival, mPFS median progression-free survival, MRD minimal residual disease, NSCLC non-small cell lung cancer, ORR objective response rate, OS overall survival, PFS progression-free survival, PR partial response, RFS relapse-free survival, RR response rate, SD stable disease, TAAs tumor-associated antigens

CAR-NK cell therapy

CAR-NK cell therapy further achieves synergistic integration of the precise targeting capacity of the CAR structure with the inherent killing ability of NK cells. 249 , 250 Studies have indicated that the CAR molecule can interact with activating receptors on the NK cell surface, achieving synergistic activation by sharing downstream signaling pathways such as those involving the DAP10 and DAP12 adapter proteins, thereby increasing tumor recognition and killing efficiency (Fig. 5b ). 251 Compared with CAR-T cells, CAR-NK cells do not typically secrete inflammatory mediators such as IL-6, significantly reducing the risk of CRS, and their non-HLA-restricted killing nature results in a very low incidence of GvHD. 252 Beyond the CAR-dependent pathway, NK cells retain the ability to recognize tumor cells through natural receptors such as DNAM-1 and NKG2D, forming multiple killing mechanisms that effectively reduce antigen escape. 253 , 254 Particularly important is the wide range of sources for CAR-NK cells, including peripheral blood, umbilical cord blood, the NK-92 cell line, and induced pluripotent stem cells (iPSCs), laying the foundation for large-scale “off-the-shelf” production. 255 , 256

CAR-NK cell therapy initially focused primarily on the treatment of hematologic malignancies. In 2020, Rezvani and colleagues reported the results of the first clinical study of cord blood-derived CD19-targeted CAR-NK cells for R/R B-cell malignancies. Among 11 patients, the ORR was 73%, with 7 patients achieving a CR. All responses were noted within 30 days of infusion, with the CAR-NK cells exhibiting low-level expansion and persistence for a minimum of 12 months. 257 A recent study reported that CD19 CAR-NK cells coexpressing membrane-bound IL-15 achieved a 30-day ORR of 62.5% and a CRR of 50% in R/R large B-cell lymphoma, with an mPFS of 9.5 months. 258 For AML, the first-in-human clinical trial of CD33-targeted CAR-NK-92 cells achieved a 60% ORR, with all responding patients achieving MRD negativity. 259 Moreover, a phase I study of a CAR-NK cell product targeting NKG2D ligands (NKX101) in patients with R/R AML demonstrated a composite CRR (CR/CRi) of 66.7% in its initial cohort, with no reported cases of CRS, ICANS, or GvHD. 260 For MM, the iPSC-derived, BCMA-targeting CAR-NK cell product FT576 achieved a 43% ORR in a preliminary assessment of its phase I trial, with a favorable tolerability profile. 261

Despite these promising clinical responses, tumor relapse driven by antigen escape remains a critical hurdle for conventional single-target therapies. To overcome this limitation, CD19/CD20 dual-target CAR-NK cells have been engineered. Studies have confirmed that these dual-target constructs, efficiently generated via mRNA electroporation, exhibit significantly enhanced cytotoxicity against lymphoma cells characterized by heterogeneous antigen expression, effectively addressing the limitations of single-antigen recognition. 262 Furthermore, this multitarget paradigm has been innovatively advanced through logic-gated architectures. A Boolean “OR” gate enabling dual-target recognition (CD33/FLT3) has been integrated to maximize the eradication of heterogeneous AML cells. This dual-targeting approach is seamlessly coupled with an EMCN biomarker-based “NOT” safety switch designed to protect healthy hematopoietic stem and progenitor cells from collateral damage. Preliminary results from a phase I clinical trial revealed that this multitargeted therapy is notably devoid of DLTs, enabling approximately 42% of patients with R/R AML to achieve durable, MRD-negative remissions with an estimated median duration of 7.6 months. 263

In the field of solid tumor treatment, CAR-NK cell therapy is gradually demonstrating breakthrough potential because of its enhanced tumor-homing ability and adaptability to the TME. The irradiated NK-92 cell platform has provided technical support for numerous studies. For instance, the administration of HER2-targeted engineered NK cells intracranially for recurrent GBM resulted in an mOS of 31 weeks, with two patients in the highest dose group achieving long-term survival (97 and 116 weeks). 264 PD-L1-targeted CAR-NK cell therapy also improved survival in patients with refractory advanced pancreatic cancer. A regimen combining it with the IL-15 superagonist N-803 resulted in an mOS of 6.2 months in patients receiving third-line therapy. 265 Additionally, local infusion strategies further highlight its application value. For example, the intraperitoneal infusion of NKG2D-targeted CAR-NK cells in patients with metastatic CRC significantly slowed ascites generation and reduced the tumor cell count, with no grade 3 or higher adverse events reported. 266

Currently, multiple “off-the-shelf” CAR-NK cell products, such as the iPSC-derived CD19 CAR-NK cell product FT522 and the clinically approved base-edited universal NK510 injection, have entered clinical development. 267 , 268 These products, which rely on standardized platforms (such as iPSCs) for scalable production, are expected to significantly overcome the cost and time bottlenecks of personalized therapy, promoting the expansion of NK cell therapy to broader clinical indications.

However, the clinical translation of NK cell therapy still faces multiple challenges. In terms of manufacturing processes, the proportions of NK cells from different sources significantly differ: peripheral blood-derived NK cells are relatively uncommon among lymphocytes (accounting for approximately 5–15%), making standardized ex vivo expansion difficult. Although iPSC-derived NK cells are conducive to scaled production, the process of their differentiation into functional NK cells is complex, and long-term culture may induce chromosomal abnormalities, necessitating strict monitoring of genomic stability. With respect to in vivo persistence and pharmacokinetics, allogeneic NK cells are susceptible to rapid clearance by the host immune system. To enhance in vivo persistence, an “immune evasion” strategy employing gene editing can be applied to knock out HLA class I/II molecules and introduce HLA-E molecules, thereby avoiding recognition by host T cells and endogenous NK cells and thus extending survival. 269 Studies have also shown that knocking out the CREM gene can significantly increase the antitumor activity and in vivo persistence of CAR-NK cells. 270 Additionally, optimizing the infusion dose combined with multiple administrations can significantly improve efficacy. 257 In terms of safety management, a careful balance between efficacy and potential toxicity is needed. Cytokine engineering strategies (e.g., the expression of membrane-bound IL-15) can increase the expansion and survival of NK cells in vivo, but the associated systemic toxicity risks must be strictly controlled. 271 Furthermore, monoclonal antibody (mAb)-based NK cell therapy serves as an indirect regulatory strategy. The application of mAbs that target inhibitory receptors on NK cells (such as NKG2A, LAG3, TIM-3, and TIGIT) relieves the suppressive effect of the TME on NK cells, thereby restoring their intrinsic activity. 272 Currently, several related mAbs (e.g., monalizumab) have entered clinical evaluation stages, demonstrating the potential for synergistic effects with cell therapies.

CAR-M therapy

Macrophages, by virtue of their inherent chemotactic and tissue-penetrating abilities as well as antigen-presenting properties, are considered promising engineered effector cells for solid tumors. 273 – 275 CAR-M therapy aims to genetically engineer macrophages, coupling their innate phagocytic and antigen-processing capabilities with tumor-specific recognition. By leveraging their antigen-presenting and proinflammatory microenvironment-remodeling functions, this approach holds promise for transforming “cold” tumors into “hot” tumors, thereby addressing the limitations of existing therapies in the treatment of solid tumors. 276 , 277

Structure and mechanism of action of CAR-M

The structure of the CAR molecule in CAR-M cells is similar to that in CAR-T cells, comprising a scFv recognition domain, a transmembrane domain, and an intracellular signaling domain. However, its signaling programming is more closely aligned with the biological characteristics of macrophages, emphasizing phagocytosis and inflammatory pathways. 106 Its design has evolved from first-generation single signaling domains to complex systems that integrate multiple signaling functions and are capable of triggering phagocytosis, amplifying inflammation, and remodeling the tumor stroma. At the phagocytosis-triggering level, this strategy utilizes ITAM-dependent signaling domains (such as CD3ζ or FcRγ) or other phagocytic receptor domains (such as Megf10) to activate phagocytic programs through the Syk kinase pathway and drive the release of cytotoxic effector molecules such as NO and ROS. 278 , 279 With respect to inflammation amplification, innate immune modules such as TLR4–TIR interact with the PI3K/AKT and NF-κB pathways, promoting the release of proinflammatory factors such as TNF-α and IL-12. This drives macrophage polarization toward the M1 phenotype and reshapes the immunosuppressive TME. 280 – 282 Furthermore, by introducing stroma-remodeling modules such as the intracellular domain of CD147, the secretion of matrix metalloproteinases (MMPs) can be induced, degrading the extracellular matrix barrier and enhancing immune cell infiltration. 283 Compared with CAR-T cells and CAR-NK cells, CAR-M cells have distinct advantages in terms of tissue penetration, survival in the stromal environment, and microenvironment remodeling, with a relatively low risk of systemic toxicity, such as CRS, making them theoretically more suitable for solid tumor immunotherapy. 284 , 285

Application of CAR-M therapy in cancer treatment

As an emerging strategy in cancer immunotherapy, the development of CAR-M therapy can be traced back to an exploratory clinical study conducted by Andreesen et al. in 1989, which employed IFN-γ-activated autologous macrophages for adoptive transfer in patients with advanced cancer. Although the approach did not induce significant tumor regression, this study was the first to validate the safety and tolerability of autologous macrophage infusion in humans. 286 In 2020, Klichinsky et al. preclinically confirmed that human HER2-targeted CAR-Ms could effectively phagocytose tumor cells and inhibit tumor growth in an antigen-dependent manner. 276 The following year, the initiation of the first phase I clinical trial for HER2-targeted CAR-M therapy (CT-0508) marked the formal entry of this technology into the clinical validation stage. 254 As research progresses, the range of targets continues to expand. For example, c-MET-targeting CAR-Ms effectively inhibited tumor progression in pancreatic cancer models and demonstrated synergistic effects with chemotherapeutic drugs such as gemcitabine, enhancing antitumor efficacy. 287

Concurrent engineering evolution is also advancing rapidly. First-generation designs focused on achieving basic CAR expression and triggering phagocytic function. 288 Second-generation designs exhibited significantly improved engineering efficiency and immune activation capability, achieved by optimizing delivery technologies such as adenoviral vectors (e.g., Ad5.F35) and electroporation and by incorporating costimulatory signaling domains such as CD28 or 4-1BB. 289 Third-generation designs further integrate cytokine modules (e.g., membrane-bound GM-CSF and IL-12) and autocrine activation circuits to increase the survival, sustained activity, and functional persistence of CAR-Ms within the immunosuppressive TME. 288

Focusing on “efficiency” and “potency”, Shen et al. developed an efficient directed differentiation system for generating CAR-Ms from human pluripotent stem cells (hPSCs) and achieved potent in vivo antitumor effects of hPSC-CAR-Ms by coactivating innate-adaptive immunity. 290 The “in situ reprogramming” strategy, which uses delivery systems to directly introduce CAR genes into TAMs within the body, provides an innovative approach to overcome bottlenecks such as long ex vivo preparation cycles and low cell yields. 291 , 292 Studies have shown that the in situ programming of CAR-Ms achieved via intraperitoneal delivery can induce robust activation of the adaptive immune system and exert synergistic antitumor effects with PD-1/PD-L1 inhibitors in treatment-resistant models. 293 In an RCC model, in situ engineered CAR-Ms expressing an IL-2R–TLR4 chimeric receptor cooperatively promoted macrophage polarization toward the proinflammatory M1 phenotype and significantly extended the median survival of mice. 294 The diversification of cell sources and manufacturing pathways further supports the clinical translation potential of CAR-M therapy. Derivation from PBMCs is currently the mainstream approach. This process involves PBMC isolation, macrophage differentiation, gene delivery, and quality control release. 295 iPSC-derived CAR-Ms demonstrate robust antigen-specific function and batch-to-batch consistency in vitro, supporting the concept of an “off-the-shelf” product. 296

Clinical data have provided preliminary validation of the safety and feasibility of CAR-M therapy. The results from the phase I clinical trial of CT-0508 announced in 2025 revealed that treatment-related adverse events were manageable. A total of 64.3% of patients experienced grade 1–2 CRS, all cases of which resolved spontaneously, and 28.6% of patients achieved SD (Table 5 ). 297 Analysis of tumor biopsies further suggested an immunologically activated state in the TME posttreatment. These results provide an important basis for subsequent dose optimization, exploration of administration routes, and screening of patient populations likely to benefit. In another phase I dose-escalation study targeting mesothelin (MSLN)-positive peritoneal metastases (including ovarian cancer and malignant peritoneal mesothelioma), the MSLN-targeting CAR-M MCY-M11 administered intraperitoneally demonstrated favorable tolerability, with no DLTs or serious neurotoxicity events reported. 298 In the field of hematologic malignancies, research on CAR-Ms is still in the early exploratory stage. Preclinical studies have confirmed the potential of CD19- or CD22-targeted CAR-Ms to eliminate leukemia and lymphoma cells, but their clinical efficacy requires further validation. 276 , 296

Despite its promising prospects, the application of CAR-M therapy in cancer treatment still faces challenges. First, unlike T cells capable of in vivo expansion, macrophages generally lack a sustained proliferative capacity, which imposes greater demands on the exposure–effect relationship and dosimetry. 299 To address this, third-generation “armored” designs, repeated administration or local/intracavitary delivery, and in vivo strategies that reprogram TAMs into CAR-Ms are expected to improve functional coverage within the tumor area. 126 Furthermore, the TME may induce an M2-like polarization bias and limit infiltration and efficacy. Enhancing adaptability requires a dual-pathway design combining “phagocytosis triggering + inflammation amplification”, prepolarization with agents such as IFN-γ or MPLA, and temporal synergy with chemotherapy-induced immunogenic cell death. 300 , 301

NKT cell therapy

NKT cells are a unique subset of lymphocytes that coexpress a TCR and the NK cell marker CD161. 302 , 303 Unlike conventional T cells that recognize pMHC, NKT cells are activated primarily through TCR-mediated recognition of lipid or glycolipid antigens presented by the MHC class I-like molecule CD1d, thereby playing a central role in tumor immune surveillance and antitumor immunity. 304 , 305 On the basis of their TCR repertoire composition and reactivity to glycolipid antigens, NKT cells are primarily classified into type I and type II. 306 , 307 Type I NKT cells, also known as invariant NKT (iNKT) cells, express an invariant TCRα chain that pairs with a limited repertoire of TCRβ chains. 308 They can be further subdivided into the following functionally distinct subsets: NKT1 (primarily producing IFN-γ, analogous to Th1), NKT2 (primarily producing IL-4, analogous to Th2), and NKT17 (analogous to Th17 and performing different immunoregulatory functions). 309 , 310 In contrast, type II NKT cells possess a diverse TCR Vα chain repertoire and primarily recognize self-lipid antigens such as sulfatide. 311 Notably, type I and type II NKT cells often play antagonistic roles in tumor immunity: iNKT cells generally mediate potent antitumor activity, whereas the activation of type II NKT cells may, in some contexts, promote tumor growth and metastasis. Together, they regulate the final outcome of the antitumor immune response. 312

iNKT cell therapy

iNKT cells exert antitumor effects in cancer immunotherapy through a dual mechanism involving direct cytotoxicity and indirect immunoregulation. 313 Studies have shown that the infiltration of iNKT cells is associated with a favorable prognosis in patients with lymphocytic leukemia, pancreatic cancer, and CRC. 314 – 316 The direct killing pathway relies on the recognition of the CD1d molecule. When CD1d is expressed on the surface of tumor cells, iNKT cells induce target apoptosis through the release of effector molecules such as perforin, granzyme B, and TRAIL, and the killing efficiency is positively correlated with CD1d expression levels. 312 , 317 Furthermore, some iNKT cells express stress-ligand receptors such as NKG2D. In the absence of CD1d on tumor cells, they can initiate NK cell-like cytotoxic responses via NKG2D engagement with its ligands, thereby eliminating CD1d-negative tumor cells, constituting a CD1d-independent backup killing mechanism. 318 With respect to indirect immunoregulation, iNKT cells can be activated by CD1d-expressing APCs within the TME, with DCs providing the strongest costimulatory signals capable of inducing a Th1-skewed response. 319 – 323 Activated iNKT cells rapidly secrete large quantities of proinflammatory cytokines such as IL-2, IL-4, IFN-γ, and TNF, creating a “cytokine cascade”, which subsequently recruits and activates effector cells such as NK cells and CD8 + T cells. 310 Simultaneously, activated iNKT cells induce DC maturation via CD40/CD40L interactions. Mature DCs express high levels of CD80/CD86 costimulatory molecules and produce IL-12, further enhancing the activity of T cells and iNKT cells themselves and forming a positive feedback loop for immune amplification (Fig. 5c ). 324

iNKT cell therapy has shown potential in cancer treatment, primarily by activating and expanding endogenous iNKT cells to induce an antitumor immune response. In patients with advanced NSCLC, a phase I trial showed that the intravenous infusion of APCs pulsed with α-galactosylceramide (α-GalCer) significantly expanded peripheral blood iNKT cells. In the cohort receiving the third dose level, the mOS extended beyond 12 months, indicating a durable immune activation effect. 325 A follow-up phase II study confirmed the efficacy of this α-GalCer-mediated endogenous iNKT cell activation approach, reporting an mOS of 21.9 months in patients with advanced NSCLC, a DCR of 42.9%, and an absence of severe treatment-related adverse events. 326 In an exploratory phase I study for head and neck squamous cell carcinoma (HNSCC), the intra-arterial infusion of Vα24 iNKT cells combined with the nasal submucosal injection of α-GalCer-pulsed APCs resulted in a PR in 3 out of 8 patients with locally R/R disease and SD in 4 patients, yielding a DCR of 87.5%. 327 Furthermore, research suggests the potential use of iNKT cell therapy in other solid malignancies, including melanoma, HCC, and GC, where it has been shown to suppress metastatic progression, with instances of long-term disease-free survival observed even in advanced-stage patients. 328 – 330

CAR-NKT cell therapy

Engineered CAR-NKT cell therapy has emerged as a promising direction in cancer treatment. 331 CAR-NKT cells can not only target TAAs via the CAR construct but also retain the endogenous ability of their TCR to recognize CD1d-lipid antigen complexes, resulting in the formation of a “CAR-TCR” dual-targeting mechanism. 332 This dual-mode recognition significantly enhances the efficiency of tumor cell clearance and reduces the risk of immune escape due to antigen loss or heterogeneity. 333 Studies have demonstrated that CD19-targeted CAR-iNKT cells can effectively eliminate CD1d-positive lymphoma cells by synergistically activating CAR signaling and the CD1d–TCR pathway. In intracranial tumor models, they breach the blood–brain barrier, achieving control of central nervous system tumors, which is difficult to attain with conventional CAR-T cell therapy. 334 Furthermore, compared with CAR-T cells, CAR-NKT cells exhibit superior tissue infiltration and can rapidly secrete Th1-type cytokines such as IFN-γ and TNF-α, activating DCs, NK cells, and cytotoxic T cells to remodel the immunosuppressive TME. 335 Safety is another notable advantage of CAR-NKT cell therapy. The inherently low alloreactivity of CAR-NKT cells results in a minimal risk of GvHD. 336 Li et al. established a technological system for the efficient differentiation and expansion of allogeneic CAR-NKT cells from HSCs. This system utilizes a triple-targeting mechanism—comprising CAR targeting, TCR recognition, and NK cell receptor-mediated signaling—to achieve multilayered, precise killing of tumor cells, thereby further enhancing the efficacy and safety of this therapy. 337

Although clinical research on CAR-NKT cell therapy is still in its early stages, several trials have demonstrated its potential in treating solid tumors such as neuroblastoma, ovarian cancer, and breast cancer. In a phase I clinical trial for relapsed neuroblastoma, GD2-targeted CAR-NKT cell therapy achieved a 75% ORR with no observed DLT or GvHD, demonstrating an excellent safety profile. 338 In ovarian cancer research, allogeneic CAR-NKT cells expressing IL-15 and targeting MSLN (Allo15MCAR-NKT cells) were able to overcome platinum resistance and significantly inhibit tumor growth in preclinical models. 339 Recent preclinical research on triple-negative breast cancer further confirmed that MSLN-targeted CAR-NKT cells derived from cord blood CD34 + HSCs achieved complete tumor eradication and 100% long-term survival in animal models without inducing significant toxicity. 339 Furthermore, CD70-directed allogeneic CAR-NKT cells (AlloCAR70-NKT cells) for RCC can simultaneously eliminate tumor cells, modulate the immune microenvironment, and deplete host-reactive T cells through a multimodal targeting mechanism. 340 In the field of hematologic malignancies, newly developed high-purity allogeneic CD33-directed CAR-NKT cells demonstrated potent tumor clearance and a high safety profile in models of AML and MDS, notably exhibiting significantly reduced off-target toxicity against healthy hematopoietic cells. 341

However, studies have shown that impaired lipid synthesis can hinder the antitumor efficacy of intratumoral NKT cells. 342 Furthermore, issues such as acquired unresponsiveness to α-GalCer, downregulation of CD1d expression on tumor cells, and the limited source of NKT cells also restrict their broad application. 343 To overcome α-GalCer immune tolerance, researchers have developed nanoparticle- or liposome-based delivery systems that can increase NKT cell activation and reduce tolerance induction. 344 Moreover, novel glycolipid compounds generated through the chemical modification of α-GalCer (such as 7DW8-5) possess superior CD1d-binding affinity and can significantly enhance the ability of NKT cells to produce IFN-γ and IL-2, thereby increasing antitumor activity. 345

Upregulating CD1d expression in target cells via transcriptional or epigenetic approaches can further optimize the recognition and clearance of tumors by NKT cells. For instance, an α-GalCer/CD1d fusion protein significantly enhanced the specific killing ability of NKT cells in a melanoma model. 346 The use of NKT cells derived from iPSCs offers a scalable approach to overcome the sourcing constraint associated with the isolation of rare NKT cells from patient PBMCs. 347 Furthermore, combinatorial regimens integrating NKT cell therapy with oncolytic viruses, chemotherapy, or radiation are promising strategies for increasing the antitumor potency of NKT cells and facilitating their infiltration into the TME. Gebremeskel et al. reported that in mouse models of breast and ovarian cancer, compared with NKT cell therapy alone, combination therapy with oncolytic vesicular stomatitis virus improved survival rates and reduced the metastatic burden. 348

DC therapy

As the most potent professional APCs in the immune system, DCs play a central role in bridging innate and adaptive immune responses. 349 , 350 DC therapy leverages their high efficiency in antigen uptake, processing, and presentation to activate specific T lymphocyte immune responses, thereby achieving precise killing of tumor cells. 351 , 352 The personalized preparation process begins with the isolation of DC precursor cells from the patient's peripheral blood, followed by the in vitro induction of differentiation. These cells are then loaded with tumor antigens (such as tumor lysates, specific antigenic peptides, or mRNA-encoded neoantigens) and stimulated to mature using signals such as TNF-α before finally being reinfused into the patient to initiate a specific antitumor immune response (Fig. 6a ). 353 Fig. 6 Dendritic cell-based cancer immunotherapy. a The standardized procedure for DC therapy involves isolating patient PBMCs, differentiating them into immature DCs, loading them with tumor antigens (e.g., neoantigens, synthetic peptides), and inducing maturation with cytokines prior to reinfusion. DC vaccines utilize advanced delivery platforms, such as mRNA-LNPs, to deliver tumor antigens directly to host APCs to initiate targeted antitumor immunity. b Within the TME, immature DCs capture shed antigens via various pattern recognition and endocytic receptors (e.g., TLRs, DEC-205, DC-SIGN), and mature DCs are characterized by the upregulation of CCR7 and MHC molecules. c Mature DCs present these antigens to T cells. Upon receiving antigen-specific signals via TCR and costimulatory signals, naïve T cells are activated and differentiate into CTLs, which subsequently execute target destruction via granzyme and perforin release. The administration of ICIs prevents T cell exhaustion and sustains robust antitumor immunity by antagonizing inhibitory signaling axes. d The antitumor response is augmented through synergistic combinations of genetic engineering (e.g., CAR-DC), adjuvant/cytokine stimulation, and ICIs or DC-T cell engagers, which collectively potentiate T cell activity and counteract the immunosuppressive TME. APC antigen-presenting cell, Cas9 CRISPR-associated protein 9, CCR7 C-C chemokine receptor type 7, cDC1 type 1 conventional dendritic cell, CTLA4 cytotoxic T-lymphocyte-associated protein 4, CTLs cytotoxic T lymphocytes, DC-SIGN dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin, DEC-205 CD205, GM-CSF granulocyte-macrophage colony-stimulating factor, ICIs immune checkpoint inhibitors, LNP lipid nanoparticle, MHC major histocompatibility complex, PBMCs peripheral blood mononuclear cells, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, STING stimulator of interferon genes, TLR Toll-like receptor, TME tumor microenvironment. Created with BioRender.com

Mechanism of action of DC therapy

DC therapy operates through multilayered, synergistic immune attack mechanisms and constitutes a key strategy in the field of cancer immunotherapy. 354 First, DCs recognize and internalize TAAs via pattern recognition receptors and process them intracellularly into peptides that bind to MHC molecules, forming pMHC complexes displayed on their surface (Fig. 6b ). 353 Mature DCs subsequently migrate to secondary lymphoid organs, where they provide signal 1 through pMHC-TCR engagement, signal 2 via costimulatory molecules such as CD80/CD86, and signal 3 by polarizing cytokines such as IL-12, leading to the full activation of naïve T cells. 355 Specifically, for CD8 + T cells, the MHC class I–peptide complexes on the DC surface directly activate them, driving their differentiation into cytotoxic T lymphocytes (CTLs) (Fig. 6c ). These CTLs then induce tumor cell apoptosis through perforin/granzyme release, activate the death receptor pathway via the Fas/FasL interaction, and secrete cytokines such as IFN-γ to suppress tumor growth. 356 Concurrently, DCs activate CD4 + helper T cells via MHC class II molecules, which amplifies the immune response and sustains immunological memory. 357

Application of DC therapy in cancer treatment

The development of DC therapy began with breakthroughs in its biological foundation. In 1973, Ralph Steinman first identified and named DCs, a groundbreaking discovery that laid the foundation for their subsequent application. 358 In 1996, the first clinical trial of a DC vaccine was initiated for immune reconstitution following prostate cancer surgery. 359 In 2010, the FDA approved the world’s first DC vaccine, sipuleucel-T (Provenge), for the treatment of mCRPC, marking the dawn of the therapeutic cancer vaccine era. Its pivotal phase III trial demonstrated that the vaccine significantly reduced the risk of death by 22%, with an mOS extension of 4.1 months. 360 In recent years, DC vaccines targeting the WT1 antigen have made significant progress. The WT1-targeting DC vaccine galinpepimut-S has shown marked efficacy against malignancies such as AML and malignant pleural mesothelioma and has received Orphan Drug Designation from the FDA. 361 , 362 The success at this stage provided a solid foundation for the subsequent development of DC-based therapeutic products.

Subsequent clinical research has confirmed the efficacy of DC therapy against various solid tumors. In melanoma treatment, the results from a phase III trial revealed that an autologous natural DC (nDC) vaccine for stage IIIB/C patients, while failing to improve the primary outcome, significantly induced antigen-specific T cell responses and was generally safe and tolerable (Table 5 ). 363 For GBM, a phase III study of the DCVax-L vaccine revealed an mOS of 19.3 months in newly diagnosed patients, with a 5-year survival rate of 13% (compared with 5.7% in the control group), and a combination therapy case in China achieved a PFS of up to 69 months. 364 In pancreatic cancer, research has indicated that a regimen combining a WT1-DC vaccine with multidrug chemotherapy enabled conversion surgery in 82% of initially unresectable patients, and long-term WT1-specific immune responses were associated with significantly prolonged patient survival. 365 Furthermore, a personalized neoantigen DC vaccine showed promising outcomes as an adjuvant therapy after surgery for esophageal squamous cell carcinoma (ESCC), with a 2-year OS rate of 91.7% in 12 patients; additionally, driver gene mutation-positive patients remained recurrence-free for nearly 3 years. 366 Clinical trials in other solid tumors, such as lung cancer, nasopharyngeal carcinoma, and ovarian cancer, have also reported positive results, including extended survival. 367 , 368

To further augment the targeted efficacy of conventional DC vaccines, following the success of CAR engineering in T cells, NK cells, and macrophages, the approach has been extended to DCs, leading to CAR-DC therapy. This innovative modality integrates the intrinsic antigen-presenting capacity of DCs with the precise targeting specificity of CARs to orchestrate robust antitumor immunity (Fig. 6d ). Currently, a combinatorial strategy utilizing both CAR-DCs and CAR-T cells is under early clinical investigation ( NCT05585996 ) for the treatment of R/R B-cell lymphoma.

Concurrently, multiple technological innovations continue to advance DC therapy. In vivo reprogramming technology, which delivers key transcription factors via adenoviral vectors or LNPs, effectively bypasses the complex traditional process of isolating and expanding DCs in vitro, offering a new pathway for large-scale production. 369 , 370 By coloading TLR agonists and tumor antigens, dual-adjuvant nanovaccine platforms can simultaneously increase DC antigen uptake and activation efficiency and precisely target lymph nodes, thereby strengthening the antigen-specific CD8 + T cell response. 371 Notably, supramolecular LNPs designed on the basis of host–guest chemistry can codeliver mRNAs encoding tumor antigens and the TLR7/8 agonist R848 into DCs, significantly enhancing their cross-presentation capacity and proinflammatory cytokine secretion. 372 mRNA vaccine technology further expands the possibilities for the in vivo modulation of DCs. 373 With respect to combination strategies, the oncolytic virus M1 strain can alleviate DC functional inhibition by downregulating the SIRPα–CD47 immune checkpoint signaling axis. 374 Furthermore, the combination of DC therapy with ICIs or chemotherapeutic agents can synergistically reverse the immunosuppressive TME, enhancing T cell infiltration and tumor-killing efficacy. Additionally, various advanced delivery systems have been developed to modulate DC functions, including dendrimers, hydrogels, and implantable scaffolds, which enable the controlled codelivery of antigens and immune adjuvants. 375 – 377

B-cell therapy

Although T cells have long been the primary focus in tumor immunology research, increasing evidence has indicated that tumor-infiltrating B lymphocytes (TIL-Bs) play a crucial synergistic role in tumor control. 378 , 379

Multifunctional roles of TIL-Bs in antitumor immunity

TIL-Bs not only mediate the killing of tumor cells by secreting highly mutated, high-affinity antibodies that mediate ADCC, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP) but also function as efficient professional APCs. They specifically recognize and internalize low-abundance tumor antigens via the B-cell receptor (BCR), present them via MHC class II molecules to activate CD4 + T cells, and promote the clonal expansion and effector differentiation of CD8 + T cells through costimulatory signals, thereby enhancing T cell-dependent antitumor immunity. 380 , 381 Within tertiary lymphoid structures (TLSs), TIL-Bs serve as core components, forming immune synapses with T follicular helper (Tfh) cells through CD40–CD40L interactions, which drive the germinal center reaction and antibody affinity maturation. 382 Simultaneously, chemokines such as CXCL13 secreted by TIL-Bs recruit CXCR5 + immune cells, which cooperate with DCs and T cells to construct a dynamic immune network that collectively shapes and maintains an immunologically active “hot” TME. 383 , 384

Single-cell transcriptomic studies have further revealed the high heterogeneity of TIL-Bs. Specifically, a CD21 low CD86 + B-cell subset demonstrates an enhanced antigen-presenting capacity, and its colocalization with T cells significantly improves tumor antigen recognition and immune attack efficacy. 385 – 387 Spatial transcriptomic analyses have revealed highly organized B-cell response zones within the TLSs of various solid tumors, such as GC and RCC, suggesting that functional interactions are facilitated by the spatial colocalization of B cells and tumor cells. 388 , 389 Recent mechanistic studies have revealed that B-cell-derived IgA antibodies can enter tumor cells via the polymeric immunoglobulin receptor (pIgR) through transcytosis, neutralize or target key signaling molecules such as RAS homologs for degradation, and increase the cytotoxic activity of CD8 + T cells. 390 Certain B-cell subsets can also directly induce tumor cell apoptosis by expressing FasL or TRAIL or by secreting granzyme B, demonstrating antibody-independent cytotoxic functions. 391 Furthermore, research has identified distinct response modes among TIL-Bs, including extrafollicular and germinal center responses. Notably, DUSP4 + atypical memory B cells (AtM B cells), which are precursors to extrafollicular-derived plasma cells, exhibit an exhausted and bystander-activated phenotype in tumors. They can promote the formation of an immunosuppressive microenvironment by secreting autoreactive antibodies and suppressing T cell function. 385

From a clinical translation perspective, the baseline density, subtype composition, and spatial distribution of TIL-Bs hold significant prognostic value. 392 , 393 Research has indicated that a plasma cell-rich TIL-B profile before treatment is correlated with improved immunotherapy outcomes in cancers such as metastatic melanoma, osteosarcoma, and ovarian cancer. 394 – 396 Pancancer analyses have further demonstrated that the abundance of TIL-Bs is inversely correlated with tumor stage, and the enrichment of TIL-Bs in “hot tumors” often indicates a more favorable prognosis. 397

Therapeutic strategies targeting TIL-Bs

On the basis of these mechanisms, TIL-B-targeted therapeutic approaches are being developed along two main lines: activating and augmenting their antitumor activity through specific modulation and selectively inhibiting regulatory B-cell (Breg) populations. 398 As an important approach to achieve precise cancer immunotherapy, ACT has demonstrated potential for clinical translation. 399 Research has indicated that the adoptive transfer of CpG oligonucleotide-activated B cells can significantly reduce the lung tumor burden in mice and increase IFN-γ secretion levels. 400 Similarly, B cells isolated from breast cancer-draining lymph nodes and activated with a combination of lipopolysaccharide (LPS) and anti-CD40 antibody exhibit antigen-specific antitumor activity and are capable of mediating the lysis of tumor cells and effectively suppressing the formation of spontaneous lung metastases. 401 Conventional anticancer therapies significantly modulate the abundance and function of TIL-Bs, with immune checkpoint blockade (ICB) exhibiting notable synergistic effects with TIL-Bs. In melanoma treatment, patients who respond to ICB show significant increases in both the TLS-to-stroma ratio and TIL-B density during therapy. 396 Animal models have further revealed that ICB activates Tfh cells, which in turn drive B cells to produce tumor-reactive antibodies, whereas depleting B cells or CD4 + T cells diminishes the antitumor efficacy of ICB. 402 , 403 Notably, the sequential administration of ICIs has shown potential for precisely modulating the TLS microenvironment. 404 In urothelial carcinoma, initial anti-CTLA-4 antibody treatment to deplete Tregs followed by anti-PD-1 antibody induces a microenvironment more conducive to immune activation. 405 However, ICB-mediated B-cell activation is a double-edged sword. The resulting hyperactivity of the germinal center may lead to autoantibody production, indicating that enhancing efficacy must be balanced with vigilance against autoimmune risks. 406

Furthermore, a variety of innovative therapies can be employed to directly shape a microenvironment conducive to the antitumor functions of B cells. Therapeutic cancer vaccines, such as the E6/E7 protein vaccine for HPV-associated tumors, have been shown to effectively recruit B cells, T cells, and DCs, leading to the formation of structurally intact TLSs at the tumor site. 407 These structures, which are functionally analogous to secondary lymphoid organs, provide an organized platform for the activation, interaction, and clonal expansion of B and T cells. Moreover, combining angiogenic modulators with ICB normalizes the tumor vasculature and induces the formation of high endothelial venules (HEVs), thereby promoting the infiltration of these immune cells. 408 , 409 The targeted delivery of cytokines or chemokines represents another significant strategy. Studies have indicated that strategies such as local injection via stromal cells or the use of engineered DCs to secrete IL-36γ can effectively induce the formation of functional TLSs and enhance antitumor immunity in preclinical models. 410 – 412 A phase I clinical trial further confirmed that the intratumoral injection of autologous DCs expressing CCL21 successfully recruited CD8 + T cells to the tumor site and elicited a systemic antitumor response. 413

Particularly noteworthy is the renewed interest in harnessing the intrinsic potential of B cells as professional APCs. “Potent activation” of B cells in vitro using CD40 agonists or TLR9 ligands can significantly upregulate the expression of MHC class II molecules and the costimulatory molecules CD80/CD86, thereby greatly enhancing their ability to activate naïve T cells and induce memory T cell responses. 414 Research by Lee-Chang et al. provides strong evidence for this: the use of IFN-γ and CD40-activated 4-1BB + B cells as a vaccine, combined with local radiotherapy, anti-PD-L1 antibody, and adoptive CD8 + T cell transfer, achieved up to 80% tumor eradication and established long-term immune memory in a GBM mouse model. 415 The therapeutic potential of antibodies produced by TIL-Bs is also of great interest. These antibodies can mediate tumor clearance by inhibiting key target proteins or mediating effector mechanisms such as ADCP/ADCC, and their Fc regions can be engineered via sialylation or glycosylation to enhance immune cell recruitment and effector function activation. 416

Early attempts to target immunosuppressive Bregs using anti-CD20 antibodies for global B-cell depletion proved ineffective and could even lead to Breg enrichment due to their relatively low CD20 expression levels. 417 , 418 Consequently, current strategies favor the use of small-molecule inhibitors (e.g., those targeting STAT3, MEK, and BTK) or combination immunomodulators to specifically block Breg differentiation or function. 419 , 420 Studies have shown that combining a STING agonist with an anti-IL-35 antibody can reduce the number of intratumoral IL-35-positive Bregs and delay tumor growth. 421 Mechanistic studies have also revealed that the B-cell-specific knockout of IL-35 promotes plasma cell differentiation and the production of antitumor IgG/IgM antibodies. 422

Although preclinical studies have demonstrated the considerable potential of B-cell therapy in cancer treatment, its translation to the clinic still faces multiple challenges. The core challenge lies in developing personalized combination strategies based on the tumor immune phenotype, the specific characteristics of the B-cell community, and the maturity of TLSs. The goal is to maximize the activation of B-cell-mediated antitumor immunity while precisely managing the potential autoimmune risks associated with overactivation, thereby safely and effectively integrating B cells into comprehensive tumor cell therapy regimens.

Stem cell therapy

The application of stem cells in cancer therapy derives from their unique biological properties, which include self-renewal capacity, multilineage differentiation potential, and specific homing to the TME. 423 Stem cells maintain their undifferentiated state and generate various functional cells through signaling pathways such as the Hippo–YAP and Wnt/β-catenin pathways. 424 Their tumor-homing ability is guided by chemokine gradients. Studies have indicated that CXCR4 overexpression enhances the homing efficiency of mesenchymal stem cells (MSCs), whereas stem cell-derived exosomes mediate tumor-specific adhesion via integrin αvβ5. 425 Furthermore, stem cells release immunomodulatory factors (e.g., TGF-β and PGE2) and bioactive substances such as exosomes through paracrine pathways, directly regulating immune responses in the TME. For instance, MSC-derived exosomes can deliver miRNA-146b to polarize macrophages toward the M2 phenotype, significantly suppressing inflammatory responses—a property strategically harnessed to mitigate treatment-induced immune toxicities such as GvHD. 426 With respect to immune cell regeneration, iPSCs can directionally differentiate into NK cells via the Notch/Wnt signaling pathway, while CD34 + HSCs can generate functional DCs upon induction with IL-3/SCF. Microenvironmental reprogramming is highly context dependent: while native MSC-derived IL-10 and indoleamine 2,3-dioxygenase (IDO) can inhibit T cell proliferation (which provides systemic support), engineered or specific stem cell subsets can reverse immunosuppression by promoting vascular normalization through matrix metalloproteinase-9 (MMP-9)-mediated degradation of the extracellular matrix, leading to increased infiltration of cytotoxic T cells. 427 , 428 Moreover, stem cell-based vaccines, which display surface antigens shared with tumor cells and combine potent innate immune activation signals, can induce broad and sustained antitumor humoral and cellular immunity, offering a novel strategy to overcome tumor immune escape. 429 Collectively, these mechanisms form a multilayered therapeutic system for stem cell therapy, encompassing targeted delivery, immune regeneration, immunomodulation, and microenvironment remodeling.

Stem cell therapy in hematologic malignancies

The history of stem cell therapy began with a conceptual proposal in the late 19th century, culminating in the successful implementation of allogeneic bone marrow transplantation in 1958, which marked the beginning of its clinical application. 430 , 431 Since the turn of the 21st century, cancer research has increasingly emphasized the application of stem cells. In particular, therapies based on MSCs have become a focal point due to their unique migratory ability and multifunctionality. 432 As of October 30, 2025, a total of 7653 stem cell clinical trials have been registered on ClinicalTrials.gov , covering more than 200 indications, including cancer, which fully demonstrates the extensive exploration and translational viability of this therapy in oncology.

Hematopoietic stem cell transplantation (HSCT) is the standard therapy for hematopoietic reconstitution following high-dose chemotherapy or radiotherapy for malignancies, with a significant breakthrough being the optimization of haploidentical transplantation techniques. 433 Adjunctive infusion of MSCs has been shown to effectively prevent and treat GvHD. A multicenter randomized trial demonstrated that the sequential infusion of umbilical cord-derived MSCs reduced the incidence of severe chronic GvHD from 17.4% to 5.4% and significantly improved GvHD-free, relapse-free survival (GRFS). 434 Furthermore, MSC infusion aids in tissue repair and enhances tolerance to high-dose chemotherapy through the secretion of immunomodulatory factors such as TGF-β and PGE2, thereby providing systemic support for patients with hematologic malignancies. 426

Advancements in engineered stem cell technology are further propelling the transition from personalized treatment to “off-the-shelf” therapies. 435 , 436 CAR-NK cells derived from iPSCs have shown substantial potential in clinical trials due to their advantages of scalable production and low immunogenicity. In a phase I clinical study, the CD19-targeted iPSC-CAR-NK cell therapy FT596 achieved a 64% ORR in CAR-T-naïve patients with B-cell lymphoma, with no DLTs observed. 256 Concurrently, CAR-engineered HSCs (CAR-HSCs), generated via lentiviral transduction, enable multilineage immune reconstitution and have been shown in preclinical models to persistently produce effector cells for more than 12 months, effectively eliminating CD19 + tumor cells. 437

Engineered MSCs as living delivery systems for solid tumors

In the field of solid tumor therapy, engineered MSCs are being increasingly developed as “living delivery systems” due to their innate tumor-homing properties and low immunogenicity. 438 This innovative approach enables the targeted delivery of therapeutic agents, including genes, prodrugs, microRNAs, oncolytic viruses, and nanomedicines, to the TME, thereby significantly increasing local drug concentrations and reducing systemic toxicity (Fig. 7 ). 439 For instance, bone marrow-derived MSCs (BM-MSCs) engineered to coexpress IFN-γ and IL-10 can effectively suppress HCC growth by modulating MAPK signaling. Moreover, engineered MSCs expressing TRAIL can potently eliminate cancer stem cell (CSC) populations in pancreatic ductal adenocarcinoma (PDAC) models, and their combination with the chemotherapeutic agent gemcitabine has been shown to synergistically enhance the apoptotic effect. 440 Fig. 7 Multifunctional mechanisms of stem cell therapy in cancer. Engineered MSCs leverage tumor-homing tropism for the site-specific delivery of therapeutic agents. Their multifunctional mechanisms include serving as living carriers for drug-loaded nanoliposomes and oncolytic viruses to exert cytotoxicity. CAR-MSCs enable precise tumor targeting and TME remodeling. Furthermore, MSCs exert potent immunomodulatory effects to activate antitumor effector cells (T cells, NK cells, macrophages) and promote tumor vascular normalization for improved drug perfusion. Their inherent regenerative properties facilitate the repair of radiation- or chemotherapy-injured tissues. Ad5 adenovirus serotype 5, CX3CL1 C-X3-C motif chemokine ligand 1, CXCL10 C-X-C motif chemokine ligand 10, HSV herpes simplex virus, MeV measles virus, MSCs mesenchymal stem cells, TME tumor microenvironment, TRAIL tumor necrosis factor-related apoptosis-inducing ligand. Created with BioRender.com

The technology of loading oncolytic viruses into MSCs capitalizes on the tumor-homing ability of stem cells to protect the virus from neutralization by antibodies. Research conducted by Darestani et al. indicated that MSCs loaded with an oncolytic measles virus effectively evaded the host immune response and significantly enhanced the antitumor effect in a liver cancer model. 441 Additionally, stem cell‒nanoparticle composite systems achieve precise drug delivery by integrating targeting and controlled-release functions, with exosomes serving as natural nanocarriers that encapsulate small interfering RNA (siRNA) and chemotherapeutic drugs. 442 Paclitaxel-loaded nanoparticles derived from MSCs significantly inhibited lung cancer growth and angiogenesis, prolonged survival, and did not induce leukopenia or hepatotoxicity. 443

CAR-MSC therapy

Recent studies have applied CAR engineering to MSCs, establishing CAR-MSC therapy as a new frontier in cell therapy (Fig. 7 ). 444 This technology aims to create a multifunctional cell therapy platform by integrating the precise targeting capacity of CARs with the inherent immunomodulatory, tissue-homing, and damage-repair functions of MSCs, thereby overcoming the limitations faced by existing CAR-T and CAR-NK cell therapies in solid tumor treatment. 445 , 446 A key safety advantage of CAR-MSC therapy arises from the low immunogenicity of MSCs, significantly reducing the risk of GvHD and laying the foundation for the development of universal, “off-the-shelf” allogeneic cell products that do not require stringent HLA matching. 447

Numerous preclinical studies have validated the therapeutic potential of CAR-MSCs in models of various tumors, including GBM, Ewing sarcoma, and AML. 448 Golinelli et al. developed a bifunctional MSC therapy by coexpressing membrane-bound TRAIL (mTRAIL) and a truncated CAR targeting GD2, achieving precise anchoring and efficient induction of apoptosis in GD2-positive GBM and Ewing sarcoma cells. 449 , 450 This strategy demonstrated GD2 expression level-dependent specific killing in vitro and has translational potential for improving local tumor treatment efficiency. In hematologic malignancies, research by Aliperta et al. revealed that genetically modified MSCs can function as “biofactories” in vivo, continuously secreting CD33/CD3 bsAbs to redirect and activate T cells for selective elimination of CD33 + AML blasts. The coexpression of the 4-1BBL costimulatory molecule further enhanced T cell-mediated antitumor efficacy. 451 Furthermore, Tang et al. utilized CRISPR/Cas9 to precisely integrate an NKG2D-CAR into iPSCs and differentiated them into uniform iPSC-derived MSCs (iMSCs), enabling specific recognition and efficient homing to solid tumors expressing NKG2D ligands. This approach provides a safe, scalable “off-the-shelf” live carrier for the targeted delivery of antitumor factors. 452 Collectively, these studies indicate that MSC-based platforms can function as modular, programmable biomanufacturing systems for precision immunotherapy. Currently, clinical studies have commenced to explore the efficacy and safety of this therapy in the field of autoimmune diseases ( NCT06435897 ).

Stem cell therapies continue to present potential risks, including immune rejection in allogeneic transplantation, tumorigenicity in the case of iPSCs, and the absence of standardized manufacturing protocols. 453 , 454 Gene editing technologies, such as CRISPR/Cas9, can improve the efficiency and purity of directed stem cell differentiation by knocking out pluripotency genes or activating specific transcription factors. Furthermore, the establishment of HLA-knockout iPSC banks facilitates the development of universal therapies, significantly reducing the risk of immune rejection. With respect to CSCs, the development of CAR-T cells that specifically target CSCs and the use of nanotechnology to achieve specific drug enrichment in CSCs hold promise for suppressing tumor recurrence and metastasis. 455

Throughout the evolution of cell therapy, various cell therapy platforms have demonstrated notable differences in biological properties, recognition mechanisms, and clinical translation prospects. Table 6 systematically compares and contrasts the strategies discussed in this review across multiple dimensions—including target recognition mechanisms, toxicity profiles, clinical maturity, core advantages, and major limitations—thus providing a comprehensive comparative overview. Table 6 Comparison of different cell therapy strategies for cancer Type Key mechanism Toxicity Clinical maturity Advantages Limitations Representative targets CAR-T MHC-independent surface antigen recognition High risk of CRS/ICANS Approved (hematologic malignancies); Phase I/II (solid tumors) Potent cytotoxicity, immunologic memory Antigen escape; lengthy and costly manufacturing; on-target/off-tumor toxicity CD19, BCMA, CD20, CD22, CD5, CD7, Claudin18.2, CD70, GPC3, CEA, HER2, MSLN TCR-T MHC-restricted intracellular antigen recognition Off-target toxicity, CRS Approved (synovial sarcoma); Phase II/III Broad target range (including neoantigens) Restricted by specific HLA haplotypes; risk of off-target toxicity due to TCR cross-reactivity WT1, PRAME, NY-ESO-1, MAGE-A4 TIL Polyclonal native TCR recognition Preconditioning-related toxicity, CRS Approved (advanced melanoma); Phase II/III Overcomes heterogeneity, superior homing capacity Limited to resectable tumors; high manufacturing failure rate; in vivo exhaustion MART-1, gp100, NY-ESO-1, MAGE γδ T/CAR-γδ T MHC-independent stress antigen recognition; inherent tissue tropism (Vδ1) Low GvHD risk; low risk of CRS/ICANS Phase I/II Dual recognition; low immunogenicity Low expansion efficiency of Vδ1 subset; activity inhibited by metabolites BTN3A1, NKG2D ligands, phosphoantigens NK/CAR-NK CAR + innate cytotoxicity receptors Low risk of CRS/ICANS Phase I/II “Off-the-shelf” potential; dual killing mechanisms; favorable safety profile Short persistence; challenging expansion/transduction; susceptible to immunosuppressive TME CD19, DNAM-1 ligands, NKG2D ligands CAR-M CAR + phagocytosis Low (no CRS reported) Phase I Remodels TME; phagocytosis Very short lifespan; may polarize to immunosuppressive M2 phenotype HER2, MSLN DC/CAR-DC Antigen presentation to activate T cells Local reaction; low systemic toxicity Approved (prostate cancer, RCC, CRC, NSCLC, ovarian cancer); Phase II/III Primes and regulates adaptive immunity Limited efficacy in immunosuppressive TME; weak immunogenicity of some vaccines Personalized neoantigens iNKT/CAR-NKT CD1d-restricted lipid antigen recognition Low (no GvHD); mild CRS Phase I Combines T cell cytotoxicity with an NK-like rapid response Rare cell population, difficult to expand to therapeutic dose GD2, CD1d-presented lipids BCMA B-cell maturation antigen, BTN3A1 butyrophilin subfamily 3 member A1, CEA carcinoembryonic antigen, CRC colorectal cancer, CRS cytokine release syndrome, DNAM-1 DNAX accessory molecule 1, GD2 disialoganglioside 2, GPC3 glypican-3, gp100 glycoprotein 100, GvHD graft-versus-host disease, HER2 human epidermal growth factor receptor 2, HLA human leukocyte antigen, ICANS immune effector cell-associated neurotoxicity syndrome, MAGE melanoma-associated antigen, MART-1 melanoma antigen recognized by T cells 1, MHC major histocompatibility complex, MSLN mesothelin, NKG2D natural killer group 2D, NSCLC non-small cell lung cancer, NY-ESO-1 New York esophageal squamous cell carcinoma 1, PRAME preferentially expressed antigen in melanoma, RCC renal cell carcinoma, TME tumor microenvironment, WT1 Wilms tumor 1

Conclusion and prospects

The successful clinical translation of cell therapies is a multifaceted endeavor requiring integrated advances in safety, efficacy, manufacturing, and regulation—not isolated technological breakthroughs alone.

Safety management: core challenges and mitigation strategies

CRS and ICANS represent significant safety challenges associated with cell therapies, characterized by high incidence rates and potentially life-threatening severity. 456 , 457 As such, they are critical areas of focus for clinical monitoring and risk management. Furthermore, the risks of GvHD and immunogenicity considerably limit the development and application of “off-the-shelf” products. 458 To mitigate CRS and ICANS, various genetic control elements, including truncated CD20, truncated HER2, inducible caspase 9 (iCasp9), and herpes simplex virus thymidine kinase (HSV-TK), have been investigated to facilitate controllable cell elimination. 459 , 460 Additionally, small-molecule tools such as protein dimerizers, degraders, and bispecific adapters can alleviate toxicity by eliminating CAR-T cells or by functionally silencing their activity. 461 , 462 Novel control systems, including optogenetic switches or hypoxia-response elements, enable the precise regulation of CAR expression or activity, thereby attenuating overactivated cell functions without inducing apoptosis. This offers enhanced controllability and reversibility compared with traditional suicide gene systems. 463 , 464 Furthermore, innovative biomaterials, such as “cytokine sponges”, can be subcutaneously implanted to adsorb excess inflammatory cytokines (e.g., IL-6) in real time, presenting a novel proactive strategy for the prevention of CRS. 465

In managing GvHD, small-molecule immunosuppressants are commonly utilized in clinical practice; however, their long-term administration may increase the risk of opportunistic infections. To mitigate this risk, novel interventions, such as the adoptive transfer of virus-specific T cells, have been implemented for infection prevention and control in immunocompromised patients. 466 , 467 Furthermore, synthetic biology-based logic-gated designs, which integrate multiple antigen recognition mechanisms, can significantly diminish the risk of on-target/off-tumor toxicity against normal tissues characterized by low antigen expression. 468 Preclinical studies have substantiated their protective efficacy in tumors exhibiting antigenic heterogeneity. 469

Efficacy optimization: ensuring sustained antitumor activity

Maintaining the functionality of therapeutic cells in vivo is crucial for sustained efficacy. However, various cell types, including T cells, NK cells, macrophages, and DCs, face challenges related to functional exhaustion and limited persistence postinfusion. 470 , 471 To address these issues, ex vivo preconditioning is typically employed to increase the persistence of therapeutic cells. Preconditioning MSCs with cytokines, small-molecule compounds, hypoxia, or biomaterials can upregulate the expression of antiapoptotic proteins such as Bcl-2, thereby improving their in vivo survival. 472 NK cells, for instance, depend on ex vivo expansion facilitated by cytokines such as IL-2 and IL-15. 473

Combination therapies and intelligent engineering are emerging as mainstream development directions. Antitumor antibodies have been shown to increase NK cell accumulation and retention at solid tumor sites, whereas the combination of ICIs with NK cells can reverse their exhausted state. In the context of DC therapy, the coadministration of TLR agonists such as CpG-ODNs or proinflammatory cytokines such as GM-CSF effectively promotes DC migration to lymph nodes, leading to more efficient activation of naïve T cells. 474 Recent studies have indicated that knocking out the SPPL3 gene and introducing an anti-CD19 CAR results in the formation of a dense glycosylation layer on the CAR-T cell surface. This “stealth” effect aids in evading host immune recognition and clearance, significantly enhancing cell persistence and antitumor activity. 475 Furthermore, innovative delivery systems, such as biomaterial-based “cytokine backpacks”, utilize nanoscale or microscale carriers to enable cells to directly transport stimulatory molecules (e.g., IL-12), presenting a novel approach for enhancing the function of nongenetically modified cells. 476 Recent research has also investigated the use of light- or ultrasound-activated proximity-labeling nanozymes to generate high-density hapten clusters locally within tumors. When combined with bsTCEs, this strategy significantly enhances the activation and cytotoxic capacity of tumor-infiltrating T cells. 477

Manufacturing and delivery: toward scalable and accessible therapies

The dense extracellular matrix and abnormal vascular network in solid tumors constitute significant physical barriers to the infiltration of therapeutic cells. 478 , 479 Critically, these structural barriers also contribute to a functionally suppressive TME characterized by, among other factors, discontinuous and low-density antigen presentation. To ensure robust activation upon encountering target cells under such suboptimal conditions, optimizing the intracellular CD3ζ signaling module or tuning the antigen-binding affinity of CAR molecules can increase their activation efficiency. 480 Furthermore, optimization of the administration route is crucial. Intratumoral and intrathecal administration routes for CAR-T cell therapies against solid tumors have been explored to bypass vascular barriers and increase local drug concentrations. 481 , 482 DCs are typically administered via intradermal, intranodal, or subcutaneous injection to increase their trafficking to lymphoid tissues. 483 Intraosseous HSC infusion has shown potential to accelerate bone marrow engraftment and reduce the risk of acute GvHD. 484 The integration of real-time imaging technologies to track in vivo cell distribution dynamics, along with the use of biomaterial carriers such as hydrogels to enhance cell homing to diseased tissues, is expected to further overcome the bottleneck of delivery efficiency. 485 Building on this foundation, innovations in smart-responsive nanodelivery systems have further enhanced the precision and controllability of treatment. pH-responsive LNPs encapsulating IL-12 mRNA can selectively release their payload in the acidic TME, activating CAR-T cells and reversing Treg-mediated suppression. 486 Furthermore, the use of CD3-targeted LNPs to codeliver CAR mRNA and the CRISPR/Cas9 gene editing module enables the simultaneous in vivo reprogramming of T cells and the knock-in of persistence-related genes such as IL-15, significantly enhancing the therapeutic effect. 487

The process of manufacturing cell therapy products directly constrains both the consistency of therapies and their clinical accessibility. Batch-to-batch variations in cell products can lead to significant fluctuations in patient responses. Particularly in MSC therapies, variables such as the donor source, tissue origin, isolation process, and storage conditions can cause substantial differences in product characteristics. 488 Furthermore, the high cost and lengthy production cycle of current autologous cell therapies, such as CAR-T cells, restrict their accessibility to broader patient populations. 489 Closed, automated production processes and allogeneic platforms based on iPSCs or cell lines are key directions for addressing this bottleneck. Notably, emerging in vivo CAR technologies utilizing delivery systems such as LNPs or viral vectors can generate CAR cell products directly within patients, significantly shortening the production cycle. 91 , 120 This strategy not only reduces costs by avoiding complex ex vivo manipulation steps but also ensures product quality consistency through standardized production processes. This technological pathway has been explored in investigational studies of cell therapies, including CAR-T cells and CAR-M cells.

Regulatory systems must coevolve with technological innovation. Currently, there is a global lack of unified classification and evaluation standards for cell therapies, which hinders the clinical translation of products and the establishment of a consensus on quality attributes. 490 The FDA has issued warnings regarding the risks of unapproved stem cell therapies, indicating an urgent need to establish a classification framework based on product characteristics and risk levels and to promote the standardization of critical quality attributes (CQAs).

Future perspectives: precision therapy driven by multidisciplinary integration

The future evolution of cell therapy hinges on the deep integration of strategies such as multiomics technologies, artificial intelligence (AI), and innovative biomaterials (Fig. 8 ). Fig. 8 Integration of emerging technologies with cell therapy for advanced therapeutic development. a Deep learning algorithms integrate multimodal clinical data—including electronic health records, multiomics profiles, dynamic biomarkers, and medical imaging—to guide personalized interventions and predict the optimal therapeutic window, balancing efficacy and toxicity. b Comprehensive multiomics analyses, encompassing DNA sequencing, mass spectrometry, and single-cell sequencing, facilitate the identification of precise therapeutic targets and expression profiles. These targets are subsequently engineered utilizing CRISPR/Cas9 systems. c Advanced 3D bioprinting generates cell line-derived and patient-derived organoids. Organ-on-a-chip microfluidic platforms simulate dynamic, systemic interactions across multiple physiological units (liver, tumor, and blood‒brain barrier) under continuous perfusion. d Innovative nanotechnology and biocompatible materials, such as solid lipid nanoparticles and stimuli-responsive smart hydrogel scaffolds, are deployed for the encapsulation of engineered cells. This strategy protects the cellular products during systemic delivery and significantly enhances their penetration capability into dense solid tumors. 3D three-dimensional, AI artificial intelligence, Cas9 CRISPR-associated protein 9, CDSS clinical decision support system, CRISPR clustered regularly interspaced short palindromic repeats, MED minimum effective dose, MTD maximum tolerated dose, sgRNA single guide RNA, t-SNE t-distributed stochastic neighbor embedding. Created with BioRender.com

At the level of clinical decision support, AI-driven deep learning of multimodal data—encompassing electronic health records, multiomics profiles, dynamic biomarkers, and medical imaging—enables the early identification of warning signals for severe cell therapy-related toxicities. These sophisticated predictive models can be seamlessly embedded into clinical decision support systems (CDSS) to facilitate the precise formulation of early intervention strategies.

Regarding therapeutic product development, to address the challenge of engineered T cell exhaustion, high-throughput sequencing and mass spectrometry-based platforms now allow for integrated single-cell analysis of the transcriptome, metabolome, and TCR clonotype, enabling ultrahigh-resolution characterization of terminally exhausted subsets. 491 Building upon this, genome-wide CRISPR/Cas9 screening technologies facilitate the systematic identification of core epigenetic or metabolic regulatory targets that drive T cell exhaustion. Targeted knockout mediated by precise gene editing can significantly reverse the exhaustion phenotype, thereby enhancing the in vivo persistence and antitumor function of adoptively transferred cells.

Moreover, advanced three-dimensional (3D) culture systems such as patient-derived organoids, tumor spheroids, and organs-on-chips provide high-fidelity in vitro platforms for microenvironmental modeling. These models accurately recapitulate the 3D spatial architecture, stromal barriers, and immunosuppressive landscapes of human solid tumors, serving as a highly predictive translational bridge for the high-throughput screening and clinical translation of next-generation cell therapies. 492

In terms of therapeutic delivery and microenvironmental modulation, the introduction of smart hydrogel scaffolds and 3D bioprinting technologies offers an alternative to the traditional systemic intravenous infusion paradigm. Encapsulating engineered immune cells within localized, biomimetic bioscaffolds not only helps overcome the dense physical barriers of solid tumors—significantly enhancing the retention, survival, and local expansion of transplanted cells at the target lesion—but also enables the spatiotemporally controlled release of immunomodulatory factors, thereby remodeling the immunosuppressive microenvironment in situ.

Ultimately, this convergent innovation model, driven by the resolution of specific clinical challenges, is poised to holistically elevate the precision, safety, and efficacy of cell therapies.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Guisha Zi, Lei Zhang, Ling Zhou.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82473220 and 82073090), the Natural Science Foundation of Hubei Province (No. 2025AFB924), the Fundamental Research Program of Shanxi Province (No. 202303021221192), the Fundamental Research Program of Shanxi Province-Free Exploration Category (No. 202303021211220), the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital (No. 2024ZHANCHI07), the Interdisciplinary Research Program of HUST (No. 2025JCYJ046), and the Special Program for Joint Cultivation of Top Medical Talents (Category A) of the Wuhan Municipal Health Commission.

Author contributions

S.W., X.P.C. and J.W. conceived and designed this project. G.S.Z., L. Zhang, and L. Zhou wrote the draft of the manuscript and constructed the figures and tables. X.S.L., L.L.W., R.X.Z. and P.D.Z. assisted in the definition of intellectual content. S.W., X.P.C. and J.W. revised the manuscript and supervised the project. All authors have read and approved the article.

Competing interests

The authors declare no competing interests.

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