Constructing the cure: engineering the next wave of antibody and cellular immune therapies.

Introduction

Immuno-oncology (IO) has undergone a remarkable transformation over the past several decades, evolving from a fringe idea to a cornerstone of modern cancer care. Figure 1 highlights the dynamic evolution of immunotherapeutic strategies from the 1950s to today. Inspired by William Coley’s pioneering work in the 1890s. 1 IO progressed through cytokine-based interventions like interleukin (IL)-2 therapy in the 1980s 2 and early tumor-infiltrating lymphocyte (TIL) protocols led by Steven Rosenberg at the National Institutes of Health (NIH), 3 laying the foundation for the checkpoint blockade revolution of the 2010s. 4 In recent years, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells 5 have gained traction alongside bispecific antibodies, neoantigen vaccines, 6 and antibody drug conjugates (ADCs). While not exhaustive, this timeline reflects the recursive cycle of innovation that continues to shape IO’s trajectory.

Over the past 15 years, IO has redefined the standard of care for many cancers, with numerous Food and Drug Administration (FDA) approvals reflecting its growing clinical impact ( figure 2 ). While this timeline reflects approvals in the USA, global efforts have further expanded IO’s impact, offering new hope for patients with otherwise refractory malignancies. Despite the transformative impact of immunotherapy, many patients fail to respond or relapse due to treatment resistance, immune-related adverse events, and the complexity of the tumor microenvironment (TME). 7 Even CAR T cells, while revolutionary in hematologic cancers, face significant obstacles in solid tumors, including antigen heterogeneity, immune suppression, and poor tumor infiltration. 8 9

In response, researchers are expanding beyond single-target modalities to develop next-generation immune constructs that integrate multiple immune functions like activating innate and adaptive cells, resisting tumor-mediated suppression, and achieving durable responses in hostile microenvironments. 10 13 Innovations designed to counter this resistance and broaden efficacy include bispecific antibodies, armored CAR T cells, synthetic cytokines, ADCs, and in vivo programming platforms. Advances in genetic engineering, synthetic biology, and artificial intelligence (AI) are accelerating the development of these multifunctional agents, paving the way for the next generation of cancer immunotherapy.

Harnessing this momentum, the Society for Immunotherapy of Cancer (SITC) has launched a strategic initiative to bring 100 new IO therapies to FDA approval within the next decade, as covered more extensively in SITC’s position article and guidelines. 14 This review explores the emerging immune constructs poised to transform cancer care, while identifying translational bottlenecks, design principles, and strategies for ensuring these therapies are safe, effective, and accessible across diverse patient populations.

Past and current therapies in immune oncology

From microbes to oncolytic viruses

The concept of using the immune system to eliminate cancer dates back centuries. The Ebers Papyrus (circa 1550 BC) documents early cancer treatments that likely induced infections to provoke tumor regression. 15 16 In the medieval period, Saint Peregrine Laziosi reportedly experienced spontaneous tumor regression following bacterial infection, 17 suggesting the body’s immune response to infection could also combat cancer. These early observations laid the groundwork for the deliberate use of pathogens to stimulate antitumor immunity.

In the late 19th century, Dr William B Coley pioneered the use of bacterial toxins to treat cancer, demonstrating that infection-induced immune responses could mediate tumor regression. 1 This concept evolved into modern oncolytic virotherapy (OV), which uses engineered or naturally occurring viruses to selectively infect and destroy cancer cells. Today, three OVs—H101, Imlygic, and Delytact—are approved globally, marking progress in the field. 18 Despite limited efficacy in metastatic settings, the next generation of OVs may offer greater systemic benefits when used in rational combinations.

Cancer vaccines

Cancer vaccines aim to train the immune system to recognize tumor antigens. 19 Prophylactic vaccines against human papillomavirus (HPV) and hepatitis B virus have dramatically reduced virus-associated cancers. Though FDA-approved, therapeutic vaccines like Sipuleucel-T have shown limited efficacy due to tumor heterogeneity and immune evasion. 20 However, newer strategies, including neoantigen-based vaccines and RNA platforms, are showing promise in early trials, 21 22 especially when combined with immune checkpoint inhibitors (ICIs), 23 25 representing a major shift in the field toward precision immune activation.

Cytokine therapy

Cytokines were among the first IO agents to receive FDA approval. High-dose IL-2 and type I interferons demonstrated proof-of-concept for immune activation in cancer. 26 33 More recent strategies use engineered cytokines, such as IL-15 superagonists (eg, N-803) and receptor-biased IL-2 variants, to improve potency and reduce toxicity. 34 39 Fusion constructs linking cytokines to antibodies or immune receptors further refine delivery and enhance safety.

ACT: lessons learned from stem cell transplant

Modern adoptive cell transfer (ACT) therapy draws inspiration from allogeneic hematopoietic stem cell transplantation (allo-HSCT) in hematological malignancies. 40 Unlike autologous transplants, which primarily serve as cytoreductive support, allo-HSCT provides potent graft-versus-leukemia effects, an early demonstration of immune-mediated tumor control. 41 Key concepts like lymphodepletion—originally developed to support donor engraftment with reduced toxicity—now underpin conditioning regimens for many forms of ACT, 42 establishing allo-HSCT as both a clinical and conceptual predecessor to ACT.

Lessons from the past: a path forward for immunotherapy

The lengthy trajectory of immunotherapy underscores its status as one of the earliest and most enduring approaches to cancer treatment, while also revealing recurring challenges. 43 45 Historically, many therapies—microbial, cytokine, or viral—lacked tumor specificity, often causing untenable levels of systemic toxicities. Additionally, early approaches focused solely on methodologies to activate the immune system, without regard to secondary immune-regulatory mechanisms exploited by tumors to evade attack. The pivotal realization that tumors employ immune-inhibitory pathways—such as programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1)—catalyzed the checkpoint blockade revolution and reframed how IO is designed. Today’s strategies emphasize precise targeting and modulation of both pro- and anti-immunogenic pathways that exist within the TME.

Summary paragraph: IO modalities by tumor type

It should be appreciated that different tumor types respond variably to distinct immunotherapy platforms. For example, ICIs dominate in melanoma and non-small cell lung cancer due to their high tumor mutational burden and pre-existing immune infiltration. 46 50 CAR T cells have revolutionized hematologic malignancies, particularly B-cell lymphoma and acute lymphoblastic leukemia (ALL). 51 TIL therapies show efficacy in melanoma and are expanding into HPV+ cancers. 52 54 Bispecific T cell engagers are gaining traction in multiple myeloma and AML. 55 56 These modality-specific successes underscore the importance of aligning immunotherapy strategies with the unique immunologic features of each tumor type.

Emerging and new constructs in immune oncology

Immune checkpoint inhibitor therapy and beyond

ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1/PD-L1 have revolutionized cancer care across a broad range of tumor types and catalyzed major advances in immunology. 57 58 However, resistance to monotherapy is common due to redundancy in inhibitory pathways. To overcome this, combinatorial strategies are being explored that target additional checkpoints (eg, LAG-3, TIM-3, TIGIT) or activate costimulatory receptors (eg, CD27, 4-1BB, CD28 OX40). 59 61 Early-phase trials are testing agonistic antibodies, occasionally paired with tumor-targeting components such as anti-CD19 or anti-fibroblast activation protein moieties. 62 64

The success of these strategies depends on factors like agent selection, timing, and sequence. For instance, dual blockade of PD-1 and LAG-3 or CTLA-4 has shown efficacy in melanoma, 65 but broader understanding of effective combinations remains nascent. A key preclinical study by Messenheimer et al revealed that the timing of PD-1 blockade can dramatically influence the efficacy of anti-OX40 antibodies, 66 highlighting the need for more mechanistic studies to optimize combination therapies.

Checkpoint blockade is now often integrated with chemotherapy and radiotherapy in first-line regimens, making it essential to understand how these combinations modulate distinct immune cell subsets. Additional strategies to improve ICI efficacy include bispecific antibodies cotargeting multiple checkpoints and Fc-enhanced antibodies, which have shown durable responses in immunologically “cold” tumors such as microsatellite-stable metastatic colorectal cancer. 67 Increasing attention is being placed on immunosuppressive myeloid populations in the TME, which contribute to immune evasion. Emerging targets include CD40, CSF-1R, CCR2, CXCR4, CD47, SEMA4D/PLXNB1, TREM2, and the LILRB family. 68 72 Moving forward, data-driven approaches will be essential to identify and prioritize the most promising immunotherapeutic combinations.

Bispecific antibodies

Bispecific antibodies are a versatile class of immune constructs that simultaneously engage a tumor-associated antigen (TAA) and an immune effector cell, enhancing specificity and therapeutic efficacy. Engineered in diverse formats, these constructs can be fine-tuned for safety, mechanism of action, affinity, valency, half-life, and manufacturability—leading to over 10 FDA approvals to date. 73 Their structural versatility has propelled bispecifics to the forefront of IO innovation.

The approval of blinatumomab (CD19/CD3) marked a milestone for bispecifics in hematological malignancies. 74 More recently, constructs targeting HER2/HER3 75 76 and Delta-like ligand 3 (DLL3) 77 have expanded into solid tumors. Trispecific antibodies are now being developed, aiming to improve immune synapse formation and incorporate additional functionalities—such as costimulation or cytokine delivery. For instance, trispecifics targeting CD3, B-cell maturation antigen (BCMA), and CD38 have demonstrated superior binding affinity and cytotoxic potency in preclinical models of multiple myeloma, outperforming their bispecific counterparts. 78 Several mechanisms of action employed by bispecific antibody therapies are illustrated in figure 3 .

Immune cell targets

Most bispecific antibodies activate T cells via CD3, enabling major histocompatibility complex (MHC)-independent tumor recognition. While this broadens tumor targeting, this strategy is not limited to tumor-specific T cells and can induce systemic toxicity. New strategies aim to fine-tune CD3 signaling or redirect activity to antigen-experienced T cells within tumors, improving specificity and reducing toxicity. Beyond CD3, bispecifics are being developed to engage inhibitory (PD-1, CTLA-4, CD73, TIGIT, TIM-3) and costimulatory (4-1BB, OX40, CD28) receptors, enabling localized immunomodulation. 79 80

Additionally, bispecific antibodies are being designed to reprogram the TME by targeting myeloid checkpoints (CD47, CD40, PD-L1, LILRB1/2, FcγRI) or by engaging innate immune cells like natural killer (NK) and γδ T cells. 81 Other constructs target immunosuppressive pathways such as TGFβ via TGFβRII to enhance antitumor immunity. 82 Dual-function bispecifics combining TAA recognition with immunomodulatory activity are also being explored to further boost efficacy.

Tumor targets

TAAs are central targets for bispecific antibodies, enabling direct tumor lysis or selective engagement of immunosuppressive cells. Frequently targeted TAAs include PSMA, 83 EpCAM, 84 HER2, 75 CD123, 85 and G protein-coupled receptor class C group 5 member D. Emerging targets, such as DLL3, STEAP1, 86 and claudins 6 87 and 18.2 are broadening bispecific antibody applicability to solid tumors. These advances reflect the expanding potential of bispecific antibodies to treat both hematologic malignancies and solid tumors.

Antibody drug conjugates and immune-stimulating antibody conjugates

ADCs represent one of the fastest-growing therapeutic modalities in oncology, with multiple approvals in recent years (see figure 1 ). 88 89 ADCs chemically link a small molecule drug to a monoclonal antibody, enabling delivery to tumor cells based on antigen recognition. This design enhances efficacy while minimizing off-target effects and systemic toxicity. Building on this foundation, immune-stimulating antibody conjugates (ISACs) have emerged to deliver immune-activating payloads—such as toll-like receptor (TLR) 90 or stimulator of interferon genes (STING) 91 agonists—directly to the TME. By leveraging antibody specificity and Fcγ receptor-mediated uptake, ISACs localize immune activation to tumor-resident immune cells such as dendritic cells (DCs) and macrophages, inducing cytokine production and facilitating antibody-dependent cell phagocytosis.

TLR-based ISACs

Efforts to incorporate TLR agonists into ISACs have focused on TLR7, TLR8, and TLR9, which are predominantly expressed in the endosomes of DCs. Many of these efforts have focused on HER2-targeting constructs. NJH395, an anti-HER2 antibody linked to a TLR7 agonist, induced type I interferon (IFN) responses but was discontinued due to severe cytokine release syndrome (CRS) and neuroinflammation. 92 Similarly, SBT6050, a pertuzumab-based HER2-targeting ISAC conjugated to a TLR8 agonist, exhibited dose-limiting cytokine-related toxicities and nominal monotherapy activity, ultimately leading to its discontinuation ( NCT04460456 , NCT05091528 ). In contrast, BDC-1001, a trastuzumab-based conjugate delivering a TLR7/8 agonist, was better tolerated at doses up to 20 mg/kg every 2 weeks and resulted in four confirmed partial responses ( NCT05954143 ). However, this program was also discontinued despite promising early signs of activity. 93 Collectively, these trials highlight the challenges of balancing potent immune activation with safety and underscore broader barriers to ISAC development, including difficulty identifying predictive biomarkers, high development costs, manufacturing hurdles, and market-related uncertainties that can hinder clinical advancement, even when early efficacy is observed.

STING-based ISACs

The STING pathway represents a promising alternative to TLRs, as it is expressed in both tumor and immune cells and drives type I IFN responses that activate innate immunity. ISACs delivering STING agonists aim to overcome the limitations of free agonists, including systemic toxicity and poor pharmacokinetics. XMT-2056, currently in Phase I trials ( NCT05514717 ), combines a novel anti-HER2 antibody—distinct from trastuzumab and pertuzumab—with a STING agonist. Preclinical studies demonstrated that XMT-2056 activates STING signaling in both tumor and myeloid cells, inducing robust antitumor immune responses while reducing systemic cytokine levels compared with free STING agonists. 94 Another clinical-stage ISAC, TAK-500, uses a cGMP-analog STING agonist (Dazostinag) conjugated to an antibody targeting CCR2-expressing myeloid cells ( NCT05070247 ). Notably, the same STING agonist is also being evaluated in an unconjugated form ( NCT04420884 ), offering a rare opportunity to compare the safety and efficacy of ISAC versus free agonist delivery. These trials may help define the future role of STING-based ISACs in the immunotherapy landscape.

Adoptive immunotherapies

Adoptive immunotherapy has transformed cancer care, with therapies like TILs, T cell receptor (TCR)-engineered cells, and CAR T cells leading the way, as illustrated in figure 4 . Despite the distinct advantages of each cell therapy strategy, common challenges remain, including intricate manufacturing processes, high costs, antigen escape, and the immunosuppressive TME. 95 Addressing these obstacles is crucial for broadening the accessibility and impact of these therapies, detailed below.

Tumor-infiltrating lymphocytes

The discovery that TILs could be isolated from tumors, expanded ex vivo with IL-2, and reinfused into patients marked a major milestone in the development of cellular therapy ( figure 4A ). 96 Early studies showed an overall response rate of 34% in patients with metastatic melanoma, 30 ultimately leading to the FDA approval of lifileucel—the first TIL-based therapy—for advanced melanoma in February 2024 ( figure 1 ). Unlike engineered cell therapies, TILs do not require genetic modification, simplifying manufacturing and preserving endogenous tumor reactivity.

TIL therapy leverages polyclonal T cells that recognize shared tumor antigens and patient-specific neoantigens, enabling durable responses in some cases. However, broader application is limited by the presence of terminally differentiated or exhausted T cells, the 4–6 week manufacturing timeline, and the requirement for surgically resectable tumors. To address these challenges, newer protocols aim to improve TIL functionality by incorporating additional cytokine support via membrane-bound IL-15 ( NCT06060613 , NCT05470283 ). Another ongoing trial ( NCT01174121 ) has shown encouraging results using neoantigen-selected TILs in combination with pembrolizumab for patients with treatment-refractory, mismatch repair-proficient metastatic gastrointestinal cancers. 97 In addition to improved cytokine support and combinatorial strategies, additional efforts to optimize TIL therapy include improved expansion protocols, epigenetic reprogramming to induce stemness ( NCT05573035 ), genetic modification to enhance antigen recognition or resist exhaustion ( NCT05361174 , NCT04426669 ), and use of biomarker-guided selection to identify patients most likely to benefit. 98 101

TCR-engineered therapies

TCR-engineered therapies emerged as an alternative to TIL therapy, enabling the generation of tumor-specific T cells from peripheral blood ( figure 4B ). Foundational discoveries on TCR antigen specificity 102 and gene transfer into T cells 103 led to the development of precision-engineered TCR-engineered T cells targeting tumor antigens presented by particular HLA molecules. 104 However, because these therapies are HLA-restricted, they are limited to patients expressing the relevant allele—most commonly HLA-A*02:01, which is present in about half of Caucasians and less frequently in Asian and African populations. 105

Early trials targeting HLA-A*02:01-restricted antigens such as MART-1, 106 NYESO-1, 107 and MAGE-A3 108 demonstrated efficacy, but also revealed safety concerns in the latter, including off-target neurologic toxicity. Like TIL therapy, combinatorial strategies with ICIs have been shown to induce more durable responses than TCR-T treatment alone, 109 with strategies for cytokine support and gene editing continuing to expand. More recently, neoantigen-specific TCR-T cells have shown promise in solid tumors such as metastatic pancreatic cancer, 110 but identifying and validating patient-specific neoantigens remains labor-intensive and costly. To address these barriers, the field is rapidly advancing antigen prediction algorithms, affinity tuning approaches to improve safety, and exploration of non-HLA-restricted TCRs such as MR1-TCRs and γδ-TCRs. Finally, efforts are underway to develop allogeneic, off-the-shelf TCR-T products to improve access and scalability. Despite these innovations, challenges in antigen discovery, TME-mediated suppression, and HLA restriction continue to limit widespread application in solid tumors. 111

CAR-engineered therapies

CAR T cell therapies have transformed hematologic cancer treatment ( figure 4B ). Seven FDA-approved CAR T cell products targeting CD19 or BCMA achieve complete response rates of 40–74% for relapsed/refractory (R/R) B-cell lymphoma, 112 71–81% for R/R B-cell ALL, 113 and objective response (OR) rates of 73–98% in multiple myeloma 114 116 ( figure 1 ). Safety has improved, though rare Parkinsonism-like neurotoxicity observed with both FDA-approved BCMA-targeted CAR T cell therapies has prompted investigation into target-specific versus off-target effects. 117 120

Expanding the use of CAR T cells beyond hematologic malignancies has been hindered by poor CAR T cell trafficking, antigen heterogeneity, and the immunosuppressive TME in solid tumors. 121 To address these challenges, ongoing strategies include chemokine receptor engineering, TME resistance mechanisms (eg, dominant negative TGFβ receptors), and logic-gated CARs for improved specificity. Early trials have shown promise for CAR T cell therapy in patients with gliomas, gastrointestinal tumors, and pediatric central nervous system tumors. 122 125 Notably, GD2-directed CAR T cells have cured a subset of patients with neuroblastoma, highlighting the potential for durable responses in solid tumors. 126 Combinatorial approaches—such as CAR T cells plus ICIs ( NCT03726515 ) or preconditioning with oncolytic viruses to improve trafficking and inflammation ( NCT05057715 )—are under active clinical investigation. The next generation of CARs incorporates cytokines, single-chain variable fragments (scFvs), or checkpoint inhibitors directly into the construct to enhance persistence and tumor remodeling; these armored CARs are discussed in the following section.

Armored T cell therapies

First-generation CAR T cells with a CD3ζ signaling domain proved feasibility but lacked efficacy, leading to second- and third-generation constructs incorporating costimulatory domains. Fourth-generation “armored” CAR T cells ( figure 4C ) enhance function through additional elements such as cytokines (eg, IL-2, 127 IL-7, 128 IL-12, 129 130 IL-15, 131 IL-18, 132 134 IL-33 127 ), decoy or inverted cytokine receptors (eg, dominant-negative TGF-βRII, 135 IL-4R/IL-7R, 136 IL-6R/IL-7R 137 ), or antibody-like proteins (eg, scFv, 138 nanobody, 139 bispecific antibodies 140 141 ). Controlled release of these payloads can be achieved through strategies such as logic-gated circuits, 142 tumor-specific promoters, 143 and non-invasive triggers like focused ultrasound, 144 enabling localized immunomodulation while minimizing systemic toxicity observed with agents like IL-12 145 and IL-15. 146

Clinically, IL-18-secreting CD19 CAR T cells achieved an 80% response rate in patients with non-Hodgkin’s lymphoma who had failed prior CAR T cell therapy, with minimal added toxicity. 147 Additional clinical trials are evaluating constructs secreting IL-15 ( NCT04381741 ), IL-7/CCL19 ( NCT04539444 ), or anti-PD-1 scFvs ( NCT05000450 ). Beyond cytokine delivery, decoy receptors help CAR T cells resist suppressive cytokines, 148 while bispecific-secreting CARs may engage bystander T cells to broaden antitumor immunity. 149 Armored TCR T cells, though less studied, show early promise in both preclinical 150 and clinical 151 settings.

Emerging non-T cell therapies

While T cell therapies dominate the field, other immune cell types are gaining traction ( figure 4D ). CAR-NK cells have shown clinical safety and efficacy in hematologic 152 and solid tumors, 153 with advantages such as reduced toxicity 154 155 and “off-the-shelf” potential, 156 though limited by shorter persistence. 157 CAR-macrophages aim to enhance phagocytosis and tumor killing; 158 early trials in HER2+ solid tumors demonstrated safety and tolerability 159 ( NCT05007379 ), with multiple studies ongoing ( NCT04660929 , NCT06224738 , NCT04405778 , NCT05164666 ). Engineered B cell therapies are being explored to improve antigen presentation (eg, peptide loading, RNA, DNA, viral vectors), deliver tumor-specific B cell receptors, and modulate immune responses. 160 Though clinical data are still limited, these strategies are supported by evidence of B cells playing a role in T cell therapies. 161 163 Engineered NK cells, macrophages, and B cells all hold significant potential but face unique challenges, including unpredictable immune behavior and reprogramming by the TME. Their comparative advantages and limitations are discussed in detail elsewhere. 160 164 165

In summary, adoptive immunotherapies show significant potential to advance medicine, but face persistent barriers, including complex manufacturing, high costs, and reliance on autologous cell products ( figure 4E ). 166 167 The extraction, genetic modification, and expansion of patient-specific cells require specialized facilities and custom workflows, inflating costs and limiting scalability. While advanced technologies like high-throughput multiomics and single-cell analysis support the need for personalized therapies, they further highlight the logistical burden of individualized therapies. To address these challenges, efforts are focused on shortening expansion timelines and developing off-the-shelf allogeneic products. Emerging technologies, such as automated GMP systems, may simplify manufacturing, while efforts to engineer CAR T cells in vivo could replace ex vivo expansion altogether. 168 Moving forward, harmonizing manufacturing standards and regulatory pathways will be critical for scaling these therapies and ensuring global accessibility.

Oncolytic virotherapy

OV leverages viruses that selectively infect and lyse tumor cells, releasing antigens that prime antitumor immune responses. These viruses—either naturally occurring or genetically engineered—represent one of the earliest biologic modalities to drive tumor regression through immune activation. While recent approvals have renewed interest in OVs, their clinical efficacy remains variable, and overcoming these limitations is a central focus of the field. 169 171 Ongoing efforts aim to enhance OV potency through improved delivery, immune modulation, and rational combination strategies.

Armed OVs

One key advantage of OVs is their genetic malleability, enabling extensive modifications to enhance therapeutic outcomes. While early studies prioritized safety, with most OVs demonstrating favorable tolerability, recent efforts have shifted to “arming” OVs with transgenes to bolster efficacy, including granulocyte-macrophage colony-stimulating factor (GM-CSF), 172 IFNβ, 173 IL-12, 174 175 and IL-2. 176 177 Additionally, ICIs such as anti-PD1 and anti-CTLA4 antibodies have been integrated into OVs to combine viral oncolysis with ICI therapy. 178 179 Multiplexed arming strategies, incorporating up to five transgenes, are being explored to further boost immunomodulation. Despite promising preclinical data, only one of the three approved OVs is armed, emphasizing the need for clinical validation of these next-generation platforms.

Systemic delivery

Patients with advanced metastatic disease—those most likely to benefit from immunotherapy—often harbor tumors that are inaccessible to direct injection. However, the three approved oncolytic agents rely on intratumoral administration, restricting their efficacy against non-injected metastatic lesions. Thus, there is an unmet need for systemically deliverable OVs capable of reaching and penetrating distant tumors. 180 One approach involves genetically modifying the viral agents to replace their natural cellular binding specificity with tumor-specific targeting. For example, adenoviruses can be engineered to swap their tropism for the coxsackie adenovirus receptor with ligands that redirect them to TAAs. 181 183 Another emerging approach leverages “Trojan horse” microbes—larger viruses or bacteria modified to carry the genome of a smaller therapeutic agent. These vehicles circulate systemically and deliver their payloads at target sites. 184 185

Combinatorial approaches

Combining OVs with other therapies is a rapidly expanding strategy to enhance efficacy through synergistic mechanisms. Traditional therapies like radiation and chemotherapy can increase viral spread and tumor susceptibility, while ICIs complement OVs by reversing immunosuppression and amplifying tumor responses. 186 188 Adoptive cell therapy has also shown promise in preclinical models, where T cells act as carriers that improve OV delivery and tumor targeting. Innovative approaches are exploring combinations of different OVs or coadministration with tumor-targeting bacteria—strategies inspired by early observations that heterogeneous infections enhance oncolytic activity.

Neoantigens: a new frontier in cancer therapy

As the field advances beyond delivery-focused strategies like oncolytic therapy, the spotlight is shifting towards precision immunotherapies that explore tumor-specific antigens, particularly neoantigens. Arising from somatic mutations, splicing errors, and post-translational modifications, neoantigens are unique to cancer cells, offering a precise target for therapies that eliminate tumors while sparing healthy tissues. Neoantigens can be induced by radiation 189 and chemotherapy, 190 potentially contributing to the efficacy of these modalities.

Recent strides in next-generation sequencing and computational biology have revolutionized neoantigen discovery. Whole-exome and whole-genome sequencing of tumor and matched normal tissues identifies mutations that may result in neoantigen formation. Sophisticated bioinformatic tools predict which mutated peptides are likely to bind MHC molecules and trigger T cell responses, while mass spectrometry offers direct identification of neoantigens by analyzing peptides bound to HLA molecules. Despite these technological advances, neoantigen identification remains challenging due to tumor heterogeneity, genetic diversity, and the cost and labor intensity of individualized profiling.

To translate neoantigen discovery into therapeutic benefit, nucleic acid-based vaccines have emerged. Messenger RNA vaccines, often formulated with lipid nanoparticles that offer protection and efficient cellular uptake, encode neoantigen-derived peptides and proteins, driving endogenous expression and robust immune activation. Using circular DNA plasmids, DNA vaccines encode TAAs or immunomodulatory agents and are showing promise in early clinical trials, especially in combination with other therapies, such as ICIs.

Cellular vaccines

Cellular vaccines leverage the immune system’s natural mechanisms to target tumors, offering a promising approach to cancer immunotherapy. Different strategies employ antigen-presenting cells, whole tumor cells, or specific peptides to elicit antitumor immune responses. DC vaccines harness the antigen-presenting capabilities of DCs, which are loaded with tumor antigens ex vivo and reinfused, to initiate robust immune responses against tumors. 191 193 Tumor cell vaccines, using autologous or allogeneic cells or lysates, present a broad spectrum of TAAs, potentially addressing the challenge of tumor heterogeneity. 194 Peptide-based vaccines, particularly those incorporating neoantigens, aim to elicit highly specific and durable T cell responses with minimal toxicity. 194

While these platforms show promise, challenges remain, including the accurate prediction of immunogenic neoantigens and the cost and complexity of personalized manufacturing. Combining neoantigen-based vaccines with ICIs or other immunomodulators is a promising strategy to overcome immune resistance and enhance therapeutic outcomes.

Leveraging artificial intelligence and machine learning to augment IO

AI and machine learning (ML) are accelerating progress in IO by uncovering novel targets, improving patient stratification, 195 and optimizing manufacturing workflows, as visualized in figure 5 . AI models can predict patient responses, 196 200 resistance mechanisms, 201 and treatment outcomes across various forms of immunotherapy.

A key application of AI is to assist scientists in understanding the fundamental biology underlying immunotherapy. For example, algorithms trained on tumor mutation and protein expression patterns offer insights into neoantigen formation and immune recognition. 201 203 In T cell biology, AI has been used to analyze TCR sequence motifs associated with antigen specificity 204 205 and tumor reactivity, 206 advancing the identification of clinically actionable TCRs. Deep learning approaches trained on large TCR-antigen datasets are now being applied to predict TCR specificity and structure–function relationships. 207 210 AI has also enhanced our understanding of CAR signaling, including tonic signaling, 211 and uncovered signaling pathways associated with therapeutic outcomes, 212 informing the design of CARs with improved functionality and safety. 213 Outside of IO, algorithms have enabled de novo design of antibodies with optimized binding to clinically relevant targets, 214 215 with similar ML approaches applied to engineer CAR scFvs with tunable affinity for better structural stability. 216 217

Finally, AI and ML are being integrated into cell therapy manufacturing, a complex process requiring high precision and reproducibility. 218 219 Algorithms are being used to automate quality control, monitor bioreactor conditions, and optimize expansion protocols for T cell products, potentially lowering costs and improving scalability.

Engaging patient advocacy to improve future therapies

Patient advocacy and diversity are essential to advancing IO and ensuring equitable access to life-saving treatments. To maximize the transformative potential of IO, researchers, clinicians, and policymakers must proactively address disparities in healthcare access. Patients from racial, ethnic, and gender minority groups, as well as economically disadvantaged backgrounds, face disproportionately high cancer mortality rates and reduced access to care. 220 222 Compounding these disparities, racial minorities remain under-represented in clinical trials, 223 limiting the generalizability and equity of new therapies. Addressing these disparities through targeted changes in research practices and healthcare delivery is essential for improving outcomes.

Increasing enrollment and retention of diverse populations in clinical trials requires proactive engagement with community leaders and patient advocates to rebuild trust in historically underserved communities. 224 225 This is particularly important for racial and ethnic groups that have experienced systemic exclusion or mistreatment by medical institutions. Expanding clinical trial sites beyond traditional hubs in the USA, UK, China, and Australia is also critical. Africa, the most genetically diverse continent, and Latin America offer significant opportunities to diversify trial populations and expand access to cutting-edge care. 226 228

Policy initiatives, such as the NIH mandate to address sex as a biological variable, 229 represent an important step. Expanding such initiatives to incentivize the inclusion of diverse patient populations will further drive equity in biomedical research. By embracing diversity and inclusion, the IO field can ensure that therapies are tailored to meet the needs of a broader range of patients while simultaneously improving access to these life-saving innovations.

Addressing remaining challenges and gaps in immune oncology treatment

Despite significant progress, substantial challenges remain in the development and delivery of IO therapies. Solid tumors continue to evade durable responses due to mechanisms such as antigen escape, tumor heterogeneity, and immunosuppressive TMEs. Additionally, many powerful therapies are hindered by toxicities arising from on-target, off-tumor interactions that damage healthy tissues.

Recent advances in synthetic biology and combinatorial immunotherapy offer new strategies for overcoming these challenges. 230 232 Innovations such as engineered cells equipped with NOT-gates 233 or antigen density sensors 234 are promising avenues for solid tumors as they aim to improve tumor specificity and reduce collateral damage to normal tissues. 235 237 Furthermore, overcoming manufacturing complexity and high treatment costs remains critical for expanding global access. Developing scalable, off-the-shelf solutions, such as edited T cells, 238 239 in vivo gene editing, 240 241 or induced pluripotent stem-cell-derived NK cells, 242 could make these therapies more widely available.

Finally, addressing economic barriers will require new policy frameworks. Alternative reimbursement models, such as outcome-based pricing, 243 and regulatory incentives for scalable technologies may help reduce cost and broaden access to these transformative therapies. 244 245 As the field continues to evolve, coordinated efforts across science, industry, and policy will be essential to realize the full potential of IO for all patients.

Future perspectives and challenges

Emerging trends in IO offer innovative solutions to longstanding therapeutic limitations. Next-generation ICIs targeting pathways like LAG-3 and TIGIT, personalized neoantigen vaccines, and advanced cell therapies—including CAR- and TCR-engineered cells targeting intracellular antigens—are expanding the therapeutic arsenal.

Technological breakthroughs, such as single-cell sequencing and AI-driven modeling, are accelerating target discovery, optimizing treatment strategies, and enabling personalized immunotherapies. These tools are catalyzing the design of rational combination therapies that integrate IO with traditional modalities like chemotherapy and radiation.

To guide development in increasingly complex landscapes, strategic frameworks are needed to prioritize immunotherapies by clinical translatability, tumor context, and cost-efficacy. Therapies offering high tumor specificity, scalability, and manageable toxicity, such as off-the-shelf bispecific or allogeneic cell products, may be favored in some settings, while high-burden, immune-infiltrated tumors may benefit most from approaches like TIL therapy combined with checkpoint blockade. Aligning therapeutic modality with tumor immunobiology and real-world feasibility will be key to effective investment and trial design.

Importantly, emerging clinical data demonstrate that high tumor burden and inflammatory status correlate with adverse events and reduced efficacy. Debulking strategies before IO, whether surgical, chemotherapeutic, or radiologic, may mitigate these risks and improve outcomes. This mirrors shifts in metastatic disease management, where integrating tumor resection with systemic IO therapies—such as surgical resection followed by immunotherapy—is being explored in cancers like colorectal and testicular malignancies.

To fully realize IO’s transformative potential, next-generation ICIs, personalized vaccines, and combination therapies must be paired with rigorous clinical investigation. These advances hold the promise to not only prolong survival and improve quality of life but also to move the field closer to curative outcomes.

Conclusions

IO has transformed the landscape of medicine, ushering in an era where the body’s immune system is harnessed to combat cancer. This review has explored key innovations, challenges, and opportunities in novel immunotherapies, reflecting on the field’s progression and its promising future. Advances in ICIs, ACT therapies, bispecific antibodies, and OVs, coupled with cutting-edge technologies like AI, high-throughput sequencing, and bioengineering are improving the specificity, precision, and efficacy of cancer treatments.

Emerging immunotherapies converge around shared themes: improved tumor specificity, refined immune engagement, and enhanced delivery to and within the TME. These advances stem from a deepening understanding of the complex interplay between the immune system and cancer, supported by advances in multiomics, synthetic biology, and next-generation manufacturing. 246 AI tools are playing an increasingly central role in identifying novel targets, optimizing combinations, and predicting patient responses, pushing the field towards true precision immunotherapy. 247 248

Nonetheless, significant challenges remain. Tumor heterogeneity and immune evasion limit the durability of response. Toxicities like CRS and the high cost of customized therapies further constrain access. Additionally, the logistics of manufacturing and delivering autologous products remain challenging to scale.

Integrating IO therapies with conventional modalities such as chemotherapy and radiation offers opportunities for synergy and improved efficacy. Personalization of therapy, exemplified by products like lifileucel, enables tailoring treatment to a patient’s unique mutational and immunologic profile, potentially overcoming treatment resistance and relapse.

The next frontier will require rational combination strategies, pairing modalities like ICIs with CAR T cells, bispecifics, oncolytic viruses, or targeted cytokine delivery, to overcome resistance, increase response, and enhance durability of remission. Adaptive trial designs, biomarker-based patient selection, and rigorous pharmacodynamic monitoring will be essential to evaluate safety, optimize dosing, and maximize synergy.

Progress will also depend on equitable access and diverse populations, which will require a collective effort from all stakeholders—patients, advocates, researchers, clinicians, policymakers, and industry leaders. Ensuring inclusivity in clinical trials, reforming reimbursement frameworks, and promoting global distribution of therapies are critical steps toward democratizing access to innovation.

As the field sets its sights on delivering 100 new IO therapies in the next decade, the collective mission remains clear: to meet real-world patient needs, expand global access, and continue the remarkable transformation of cancer care into an era of durable, life-saving immunotherapies.

Acknowledgements

The authors wish to thank SITC staff including Mary Dean and Christina Mooney for project management and Kaitlin Johnson, PhD for editorial assistance. Additionally, the authors thank SITC for supporting the manuscript development. Figures 1 and 3 created in BioRender Wittling, M (2025) https://BioRender.com/j51e416 and Ramos, H (2025) https://BioRender.com/eu82g3g .

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Patient consent for publication: Not applicable.

Ethics approval: Not applicable.

Provenance and peer review: Not commissioned; externally peer reviewed.

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