The evolving global landscape of first-in-class oncology drug innovation.

Introduction

Owing to its devastating nature and substantial global disease burden, cancer remains a central priority in pharmaceutical research and development (R&D). In recent years, oncology has consistently led all therapeutic areas in terms of the number of newly approved drugs. 1 – 3 A remarkable proportion of these approvals are first-in-class (FIC) medicines—defined as the first globally approved products with either novel molecular targets or mechanisms of action (MoA). 4 These trailblazing drugs offer therapeutic opportunities for diseases with previously unmet medical needs and serve as powerful catalysts for continued biomedical innovation. By engaging previously unexplored biological circuits, FIC therapies have not only deepened insights into cancer pathogenesis but also inspired new paradigms in therapeutic development. Such breakthroughs are the products of decades of global scientific endeavors—rooted in the relentless pursuit of novel pathogenic mechanisms and empowered by transformative technological advances. This path has been far from linear and is marked by iterative cycles of hypothesis, failure, and refinement. 5 , 6 Nonlinear progression has fundamentally transformed the architecture of cancer care, anchoring a shift toward mechanism-based, modular intervention strategies.

The history of cancer therapy is defined by successive waves of innovation, each redefining the therapeutic calculus and broadening clinical horizons. From the early days of broadly cytotoxic chemotherapy, through the era of molecularly targeted therapies and immuno-oncology, to the modern age of engineered cell therapies, FIC therapeutics have consistently marked pivotal transitions in oncology (Fig. 1 ). Early FIC medicines such as mechlorethamine 7 (DNA alkylation), methotrexate 8 (folate antagonism) and 5-fluorouracil 9 (pyrimidine synthesis inhibition) laid the biochemical foundation of cytotoxic chemotherapy with features of poor selectivity and systemic toxicity. The next inflection point arrived with molecularly targeted therapies in the early 2000s, ushered in by imatinib, 10 the first approved tyrosine kinase inhibitor, which selectively targeted the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion protein in chronic myelogenous leukemia (CML), establishing a model for rational, mutation-specific drug design. This transition toward molecularly guided precision treatments continued with agents such as trastuzumab, which targets human epidermal growth factor receptor 2 (HER2) in breast cancer, 11 and larotrectinib, which is a tumor-agnostic therapy for tumors with neurotrophic receptor tyrosine kinase (NTRK) gene fusions 12 . Yet precision targeting alone has proven insufficient, as tumors have evolved resistance or evaded pathway inhibition. This realization catalyzed the rise of immuno-oncology, referring to cancer not solely as a genetic disease but also as an immune-evasive entity. 13 Landmark agents include several immune checkpoint inhibitors (ICIs), such as ipilimumab—the first cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor, nivolumab—the first programmed cell death protein 1 (PD-1) inhibitor, and atezolizumab—the first programmed cell death ligand 1 (PD-L1) inhibitor, which has demonstrated the possibility of durable tumor control via immune modulation. 14 The subsequent approval of cellular therapies, such as tisagenlecleucel, 15 which was approved in 2017, marked a mechanistic leap—harnessing ex vivo engineered T cells as living drugs capable of direct and sustained cytotoxicity against hematologic malignancies. Unlike checkpoint inhibitors that disinhibit endogenous T cells, chimeric antigen receptor (CAR)- T cell therapy imposes a synthetic immune logic, enabling antigen-specific killing irrespective of host priming. Concurrently, attention has turned to the tumor microenvironment (TME), which is a dynamic niche that governs immune exclusion, stromal resistance, and metabolic constraints. While early agents such as bevacizumab 16 (anti-vascular endothelial growth factor, anti-VEGF) disrupt angiogenic signaling, newer strategies aim to rewire stromal-immune interactions and metabolic fluxes. This evolution reflects a conceptual shift from targeting tumor cells in isolation to orchestrating systemic, ecosystem-level interventions. 17 Fig. 1 Landmark first-in-class drug approvals illustrating key mechanistic breakthroughs across successive waves of cancer therapy innovation

To provide a comprehensive overview of global innovation trends in oncology drug development, this review focuses on FIC therapies—defined as the earliest globally approved drugs with novel targets or MoA—and potential FIC (PFIC) candidates currently under clinical evaluation with the potential to attain FIC designation upon approval. Building on methodologies established in prior literature, 4 , 18 , 19 this analysis applies an adapted analytical framework to identify and characterize both approved and investigational FIC agents, with full details on the classification criteria, data sources, and analytical procedures provided in the Supplementary Methods . By integrating both marketed and investigational agents, this Review delineates the longitudinal evolution of FIC innovation trajectories in cancer therapeutics. In particular, it explores key drivers, such as the emergence of novel molecular targets and the rise of enabling therapeutic platforms, which collectively reshape the scope, mechanisms, and clinical potential of FIC interventions. These two dimensions intersect to define four distinct innovation archetypes, allowing systemic dissection of divergent developmental trajectories and translational bottlenecks across the FIC landscape. Furthermore, it analyzes enduring challenges and emerging opportunities that continue to shape the FIC landscape paradigm. Through this structured and forward-looking synthesis, we aim to inform future research priorities, accelerate clinical translation, and support policy efforts that expand access to transformative cancer therapeutics worldwide.

Global landscape and overall approvals

Overall approvals of FIC oncology medicines

Global oncology drug innovation has entered a stage of sustained and unprecedented acceleration, as reflected in the increasing number of newly approved therapies worldwide. From 2019 to 2024, the global portfolio of oncology therapeutics expanded at an average annual rate of ~9%. 20 As the primary agency for new drug approvals, the U.S. Food and Drug Administration (FDA) reported a surge in oncology approvals—from 3.4 per year (2000–2004) to 15.2 per year (2017–2022), marking a 447% increase. 21 This growth underscores both improved pipeline productivity and the broader adoption of regulatory innovations that prioritize early access to therapeutics addressing high unmet needs. In support of this shift, clinical trial activity in oncology has remained at historic highs. In 2022, the number of initial trials increased by 22% relative to that in 2018, and in 2023 alone, more than 2000 new trials exploring innovative cancer therapies were launched worldwide. 22 Amid this broader surge in oncology approvals, FIC therapies have shown a similar upward trajectory of expansion (Fig. 2a ). Between 2009 and 2024, a total of 93 FIC oncology products received marketing approval in at least one country, with a significant upward trend over time (Spearman p = 0.011) and a median of six approvals per year (interquartile range [IQR]: 3-8). This pattern reflects a deeper strategic shift in oncology R&D—from incremental optimization of existing agents toward the systematic pursuit of previously untargeted molecular pathways and therapeutic mechanisms. Fig. 2 Global landscape of approved first-in-class (FIC) and potential FIC (PFIC) oncology products, 2009–2024. a Annual counts of newly approved FIC drugs and potential FIC drugs. The entry year of PFIC oncology was defined by the initiation year of the earliest trial. b Primary indications associated with initial approvals of FIC drugs across approval years. c Innovation archetype classification of FIC and PFIC drugs on the basis of the nature of novelty introduced, categorized as new targets, new mechanism of action, multitarget strategies or new mutation subtypes. d Geographic distribution of first global approvals of FIC drugs, stratified by region and approval year

Geographic analysis of FIC approvals from 2009 to 2024 underscores the United States (75, 80.6%) as the leading launch market, followed by Japan (10, 10.8%), China (5, 5.4%) and Europe (3, 3.2%) (Fig. 2d ). The U.S. leadership is supported by the FDA’s robust and adaptive regulatory architecture, which features a comprehensive suite of guidance documents and expedited review mechanisms responsive to emerging scientific paradigms. Among these, breakthrough therapy designation 23 facilitates close regulatory engagement, and accelerated approval allows earlier market access on the basis of surrogate endpoints that are reasonably likely to predict clinical benefit. 24 In Japan, several first approvals were enabled by the Sakigake Designation, 25 which was introduced in 2015 to promote domestic innovation. This program offers priority consultation, preapplication review, and shortened review timelines, often positioning Japan as the first launch country. In China, the majority of FIC approvals occurred after 2020, bolstered by a series of regulatory reforms introduced by the National Medical Products Administration (NMPA), including conditional approval and breakthrough therapy designations. 26 , 27 These pathways have catalyzed a strategic pivot from me-too and fast-follow approaches to globally competitive FIC innovation, 28 signaling the maturation of domestic innovation capacity. 29 Although Europe accounted for only three first approvals, the European Medicines Agency (EMA) often serves as the second major regulatory body to authorize first-in-class oncology therapies after the FDA, typically within one year of FDA approval. 30 This allows timely access across the European Union (EU) through a centralized and harmonized review process.

Origins of innovation in FIC oncology drugs

To dissect the mechanistic basis of FIC advances, this study categorized these FIC oncology drugs into four archetypes of innovation: 1) agents that target novel molecular targets, 2) agents that are designed for specific mutation subtypes, 3) agents that introduce new modalities or mechanisms of action, and 4) agents that engage multiple established targets in new configurations (Fig. 3 ; Table 1 ). Among the 93 FIC therapies, over half (52, 55.9%) were driven by target novelty, underscoring target discovery as the linchpin of oncologic innovation (Fig. 2c ). Several landmark examples have catalyzed subsequent waves of extensive research and pipeline expansion. The approvals of nivolumab and pembrolizumab in 2014, the first two PD-1 ICIs, marked a mechanistic inflection point in immuno-oncology, validating immune checkpoint blockade as a broadly applicable strategy across diverse tumor types. 31 , 32 By 2021, clinical trials involving anti–PD-1/PD-L1 antibodies had surpassed 5600, positioning this axis not only as a dominant monotherapy but also as a modular backbone in combination regimens and next-generation designs. 33 Over 75% of these trials involved combinations with chemotherapy, targeted therapies, or additional immune modulators. 33 More recently, molecular fusion strategies of PD-1/PD-L1 blockade with other functional modules have yielded bispecific constructs such as cadonilimab (PD-1/CTLA-4) and ivonescimab (PD-1/VEGF), which are designed to spatially or functionally cotarget tumor immunobiology. Another landmark was the approval of olaparib, the first poly (ADP‒ribose) polymerase (PARP) inhibitor, 34 which provided the first clinical validation of synthetic lethality. By selectively targeting DNA repair vulnerabilities in tumors with breast cancer susceptibility gene 1/2 ( BRCA1/2) mutations, olaparib demonstrated that exploiting cancer-specific liabilities—rather than classical oncogenic drivers—could yield effective and durable responses. 35 Its success ignited a wave of follow-up PARP inhibitors, including niraparib, rucaparib, and talazoparib, and positioned synthetic lethality as a viable development paradigm. Building on this foundation, researchers have expanded this concept to include other DNA damage response targets, such as ataxia-telangiectasia-mutated (ATM), ATM and Rad3-related (ATR), checkpoint kinase 1/2 (CHK1/2), and WEE1 G2 checkpoint kinase (WEE1), with the aim of extending therapeutic reach across a broader spectrum of genomic instability. Together, these advances exemplify how deepening mechanistic insights into tumor biology can redefine therapeutic possibilities and reshape the molecular taxonomy of cancer. Fig. 3 Four archetypes of innovation in first-in-class oncology medicines. FIC oncology drugs are classified into four categories: new targets, new mutation subtypes, new mechanisms of action, and new multi-target strategies. 1) New targets (green, upper left)—drugs that engage previously untargeted molecular entities such as novel receptors, enzymes, or signaling mediators: novel molecular and cellular targets identified for therapeutic intervention, such as immune checkpoints (e.g., PD-1, CTLA-4, and CD47), receptor tyrosine kinases (e.g., FGFR, EGFR, and ALK), and other tumor-associated antigens (e.g., HER2, BCMA, and CD38). In addition, several emerging targets, such as HER3, CD70, and CD28, are under investigation as potential drivers of future first-in-class drugs. 2) New mutation subtypes (blue, upper right) — agents designed to address resistance mutations or biomarker-defined patient subsets within known oncogenic pathways: genetic variants driving oncogenesis, exemplified by activating mutations in EGFR (e.g., T790M), highlighting the role of precision oncology in targeting molecular subgroups. 3) New mechanisms of action (orange, lower left)—therapies that apply emerging modalities such as bispecific antibodies, ADCs, protein degraders, and cell therapies: diverse therapeutic modalities beyond conventional small molecules and antibodies, including nucleic acids, antibody–drug conjugates, proteolysis-targeting chimeras (PROTACs), gene therapy, and cell-based therapies such as CAR-T cells. 4) New multi-target strategies (purple, lower right)—agents that simultaneously act on multiple established targets to overcome redundancy, clonal evolution, or tumor heterogeneity: approaches that simultaneously engage multiple pathways or immune checkpoints, exemplified by bispecific antibodies such as ivonescimab (PD-1/VEGF dual blockade), to overcome resistance and enhance antitumor efficacy. Together, these innovation directions underscore the expanding scientific and technological frontiers that shape the pipeline of FIC oncology medicines. This figure was created at https://BioRender.com Table 1 A framework of innovation archetypes in first-in-class oncology drugs Innovation archetypes Description 1. New targets (previously unexploited molecular targets) These therapies exploit biological targets—such as surface receptors, enzymes, or signaling mediators—not previously addressed by any approved therapy. Innovation in this category stems from fundamental advances in cancer biology and expands the druggable mechanisms. Example: Olaparib , the first PARP inhibitor to exploit synthetic lethality in BRCA-mutant cancers. 2. New mutation subtypes (genotype-specific precision therapies) These therapies selectively target oncogenic variants—such as resistance mutations or biomarker-defined subpopulations—within known pathways. Innovation arises from the application of precision medicine principles, delivering high therapeutic specificity and efficacy in genetically stratified patient populations. Example: Osimertinib , a third-generation EGFR inhibitor specifically designed to overcome T790M-mediated resistance. 3. New mechanisms of action (emerging therapeutic modalities or functional strategies) These therapies introduce novel therapeutic platforms—such as ADCs, bispecific antibodies, proteolysis-targeting chimeras (PROTACs), or mRNA-based therapeutics—that confer distinct modes of action, delivery, or immune engagement. Innovation lies not in the biological target itself, but in the mechanistic reconfiguration of how the therapeutic effect is achieved. Example: Zanidatamab , a bispecific antibody engaging two HER2 epitopes to enhance receptor clustering and antibody-dependent cellular cytotoxicity (ADCC). 4. New multi-target strategies (integrated converging multiple targets) These therapies simultaneously modulate multiple molecular targets strategies—either within a single agent or through modular constructs—to address pathway redundancy, clonal evolution, and tumor heterogeneity. Innovation stems from the rational integration of mechanisms to maximize durability and broaden patient applicability. Example: Entrectinib , a small-molecule tyrosine kinase inhibitor that targets TRK (NTRK1/2/3), ROS1, and ALK fusions to block oncogenic signaling across fusion-driven tumors. This framework categorizes FIC oncology drugs into four distinct innovation archetypes, based on how therapeutic novelty is introduced—via new biological targets, novel mechanisms, mutation-specific precision, or multitarget approaches. These archetypes facilitate the identification of innovation trajectories and support a structured understanding of historical patterns and emerging trends in oncology drug development

A second archetype involves therapies developed for mutation-defined resistance or vulnerabilities, currently comprising four FIC approvals (4.3%). Osimertinib, 36 a selective epidermal growth factor receptor (EGFR) T790M inhibitor, exemplifies how targeted molecular precision can re-establish therapeutic control in resistant non-small cell lung cancer (NSCLC). Similarly, pirtobrutinib, a reversible Bruton’s tyrosine kinase (BTK) inhibitor, retains activity in C481S-mutated tumors resistant to covalent BTK inhibitors, illustrating the therapeutic value of targeting acquired resistance mutations through tailored design. 37

New modalities also represent a major vector of innovation (23/93, 24.7%), often enhancing or repurposing validated targets by emerging mode-of-action paradigms. Blinatumomab, the first bispecific T-cell engager (BiTE) 38 approved in 2014, redirects CD3 + T cells to eliminate CD19 + malignant B cells—marking a mechanistic departure from conventional monoclonal antibodies and paving the way for subsequent T-cell–redirecting therapies. Its success has led to a new wave of T-cell–redirecting therapies, including next-generation BiTEs, trispecific antibodies, and engineered platforms such as CAR-T and T-cell receptor (TCR)-based bispecifics, all aimed at enhancing tumor selectivity, in vivo persistence, and resistance mitigation. 39 A parallel trajectory of modality-driven innovation is exemplified by HER2-targeted therapies. Following the introduction of trastuzumab—the first HER2-targeting monoclonal antibody—in 1998, a sustained pipeline of HER2-directed strategies has emerged across increasingly sophisticated therapeutic formats. 40 For example, ado-trastuzumab emtansine (approved in 2013), the first HER2-targeted antibody‒drug conjugate (ADC), enabled the delivery of a selective cytotoxic payload to HER2-expressing tumors. More recently, two bispecific antibodies were approved in 2024—zanidatamab, a biparatopic HER2-binding antibody, 41 and zenocutuzumab, a HER2/HER3 bispecific antibody designed to inhibit neuregulin 1 (NRG1) fusion–driven signaling 42 —further highlighted the role of HER2 as a versatile therapeutic anchor for next-generation modular constructs. These advances underscore the capacity of modality innovation to expand the precision, scope and modularity of targeted cancer therapies.

Finally, the multitarget strategy group (14/93, 15.1%) reflects a growing emphasis on polypharmacology as a means to address pathway redundancy and intratumoral heterogeneity. Entrectinib, a selective inhibitor of tropomyosin receptor kinase A/B/C (TRK A/B/C), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), and anaplastic lymphoma kinase (ALK), exemplifies this trend by simultaneously targeting several oncogenic kinases implicated across tumor histologies. 43 This approach not only broadens the pool of eligible patients by encompassing multiple actionable alterations but also mitigates the emergence of resistance driven by pathway compensation or clonal diversification. Other examples include cabozantinib and lenvatinib, both of which inhibit multiple receptor tyrosine kinases and are approved across diverse solid tumors, highlighting the clinical utility of multitargeted inhibition in overcoming therapeutic escape mechanisms.

Collectively, these four archetypes exemplify distinct yet complementary routes to first-in-class innovation—ranging from expanding druggable target space and refining precision through mutation-specific inhibitors to reengineering validated biology through novel modalities and leveraging polypharmacology to counter tumor complexity. Together, they constitute a modular and mechanistically driven framework for driving forward the next generation of oncology therapeutics.

Indication landscape of approved FIC oncology drugs

The initial approvals of FIC oncology drugs span a diverse spectrum of malignancies, with notable clustering in specific tumor types (Fig. 2b ). Among the 93 FIC approvals analyzed, the most frequent initial indications included lymphoma (15/93, 16.1%), leukemia (12/93, 12.9%), NSCLC (11/93, 11.8%), multiple myeloma (8/93, 8.6%), melanoma (7/93, 7.5%), and breast cancer (6/93, 6.5%). Across tumor types, R&D efforts are broadly aligned with disease burden, as measured by disability-adjusted life years (DALYs). 44 This trend is reflected in our dataset, where lung and breast cancers rank within the top six indications for FIC approvals. However, hematologic malignancies—despite their comparatively lower DALY burdens—account for a disproportionately large share of FIC approvals. Beyond these dominant indications, 36.5% of FICs target a wide range of solid tumors, including gastric, bladder, biliary tract, and cervical cancers. In the following sections, we discuss the biological and strategic factors underpinning these trends in hematologic and solid tumors, respectively.

Drivers of innovation in hematologic malignancies

Hematologic malignancies—including lymphoma, leukemia, and multiple myeloma—account for nearly 40% of first-indication FIC approvals, a disproportionately high share relative to their incidence and mortality burden. This trend may reflect a convergence of biological tractability, clinical trial feasibility, and regulatory flexibility uniquely associated with hematologic cancers.

From a biological standpoint, hematologic malignancies are frequently characterized by well-defined, recurrent molecular alterations, making them particularly amenable to precision targeting. 45 In acute myeloid leukemia (AML), for example, up to 90% of patients harbor identifiable genetic drivers, enabling the development of multiple FIC therapies, such as venetoclax, the first-in-class B-cell lymphoma 2 (BCL-2) inhibitor 46 and gilteritinib, a selective FMS-like tyrosine kinase 3 (FLT3) inhibitor. 47 In CML, the discovery of the BCR-ABL fusion gene led to the approval of imatinib, a landmark FIC therapy that defines molecularly targeted treatment. 48 Similarly, aberrant B-cell receptor signaling has been successfully targeted in multiple B-cell malignancies, exemplified by ibrutinib, the first BTK inhibitor initially approved for chronic lymphocytic leukemia (CLL) and later expanded to mantle cell and marginal zone lymphoma.

The introduction of novel therapeutic modalities—particularly cell and gene therapies—has further accelerated first-in-class innovations in hematologic malignancies. These diseases often express lineage-restricted surface antigens that enable highly selective targeting with minimal on-target off-tumor toxicity. 15 , 49 Furthermore, blood cancers are typically disseminated and accessible through the circulation, allowing engineered immune cells to reach tumor cells without needing to overcome physical barriers. The success of CD19-targeted CAR-T-cell therapies has led to a wave of engineered cell products, including idecabtagene vicleucel, the first B-cell maturation antigen (BCMA)-targeting CAR-T cell. 50 Building on these advances, next-generation CAR-T-cell therapies are exploring targets such as CD20, CD22 and CD123.

Compared with solid tumors, hematologic cancers benefit more from robust surrogate endpoints—such as the objective response rate (ORR) and complete remission (CR)—which are strongly correlated with long-term survival outcomes. In acute leukemia, achieving minimal residual disease (MRD)-negative CR predicts relapse-free and overall survival. 51 , 52 In multiple myeloma, response depth—ranging from very good partial response (VGPR) to stringent complete response (sCR)—correlates with durable survival benefit. 53 These reliable end points enable smaller, faster clinical trials with interpretable outcomes and support the use of expedited approval pathways. In our dataset, 82.8% (29/35) of first-in-class drugs for hematologic indications were approved on the basis of early response metrics prior to the availability of mature survival readouts.

Drivers of innovation in solid tumors

Among solid tumors, lung cancer and breast cancer have been focal points for FIC innovation, reflecting not only their high global disease burden but also the depth of molecular characterization achieved through decades of research. 54 , 55 In NSCLC, the discovery of key oncogenic drivers—such as EGFR mutations (e.g., exon 19 deletion, L858R, T790M, C797S), ALK, ROS1, rearranged during transfection (RET) and NTRK gene fusions, B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutations, mesenchymal epithelial transition factor (MET) exon 14 skipping alterations, Kirsten rat sarcoma viral oncogene homolog G12C (KRAS G12C) mutations, and HER2 insertions—has enabled a broad array of targeted FIC therapies and biomarker-guided patient stratification. 56 Similarly, in breast cancer, molecular profiling on the basis of estrogen receptor or progesterone receptor (ER/PR) status, HER2 amplification, and alterations in genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (e.g., H1047R), BRCA1/2, estrogen receptor 1 (ESR1) (e.g., Y537S, D538G), Akt serine/threonine kinase (AKT1), phosphatase and tensin homolog (PTEN) loss, and fibroblast growth factor receptor 1 (FGFR1) amplification has facilitated the development of multiple novel targeted and endocrine-based FIC agents. 57

The success of these targeted agents has facilitated indication expansion across tumor types sharing similar molecular features. HER2-targeted therapies, for instance, have extended beyond breast cancer into HER2-positive gastric and biliary tract cancers, 58 while EGFR inhibitors are being explored in glioblastoma and cholangiocarcinoma. 59 These developments underscore the translational impact of mechanism-driven strategies that transcend tissue origins. This paradigm shift has paved the way for tissue-agnostic therapies guided solely by molecular features. Following pembrolizumab’s landmark approval in 2017 for microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) tumors, the first FIC agent in our dataset to receive a pancancer indication was larotrectinib in 2018 for NTRK fusions. This was followed by the approval of dabrafenib plus trametinib for BRAF V600E-mutated solid tumors. These breakthroughs continue to motivate the exploration of tissue-agnostic targets, supported by adaptive trial designs such as basket and umbrella trials. 60

In addition to molecularly targeted therapies, immuno-oncology has reshaped the FIC landscape in solid tumors. Melanoma emerged as a pivotal model due to high tumor mutational burden (TMB) and intrinsic immune responsiveness. 61 , 62 Furthermore, the superficial and accessible nature of skin lesions facilitates frequent sampling and real-time monitoring of treatment response, enabling early proof-of-concept trials for immunotherapies. 63 The unique biological and clinical profile of melanoma has led to multiple approvals: interleukin-2 (first cytokine therapy); ipilimumab (first CTLA-4 checkpoint inhibitor); pembrolizumab and nivolumab (first PD-1 checkpoint inhibitors); and talimogene laherparepvec (T-VEC, first oncolytic virus therapy). These breakthroughs subsequently paved the way for broader application beyond melanoma. Among them, pembrolizumab has achieved unprecedented versatility, securing at least 40 FDA-approved indications across solid tumors and hematologic malignancies. 64

FIC oncology drug approval in 2024

The year 2024 marked a record high in FIC oncology drug innovation, with 12 therapies receiving global approval (Table 2 )—9 approved by the US FDA, 2 by Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), and 1 by China’s NMPA. By applying our novel archetype framework, these approvals encompass a spectrum of innovations: seven agents introduced previously unexploited molecular targets, including mixed lineage leukemia protein-1 (MLL1), claudin 18.2 (CLDN 18.2), delta-like canonical Notch ligand 3 (DLL3), HER2/HER3, melanoma-associated antigen A4 (MAGE-A4), interleukin-15 receptor α (IL-15Rα), and isocitrate dehydrogenase 1/2 (IDH1/2); four leveraged novel mechanisms or platforms, such as bispecific antibody, tumor-infiltrating lymphocyte (TIL) therapy, and one drug was specifically engineered to address a genetically defined resistance subtype. Table 2 First-in-class approvals in 2024 Drugs Mechanism Approval time Region of first approval Lifileucel TIL therapy 2024/2/16 United States Zolbetuximab anti-CLDN18.2 monoclonal antibody 2024/3/26 Japan Nogapendekin alfa inbakicept IL-15/IL-15Rα-Fc fusion protein 2024/4/22 United States Tovorafenib Raf kinase inhibitor 2024/4/23 United States Tarlatamab anti-CD3/DLL3 bispecific antibody 2024/5/16 United States Ivonescimab anti-PD-1/VEGF-A bispecific antibody 2024/5/21 China Afamitresgene autoleucel TCR-engineered T-cell therapy 2024/8/1 United States Vorasidenib IDH1/IDH2 inhibitor 2024/8/6 United States Tasurgratinib FGFR3/FGFR2/FGFR1 inhibitor 2024/9/24 Japan Revumenib menin/MLL1 protein–protein interaction inhibitor 2024/11/15 United States Zanidatamab anti-HER2 bispecific antibody 2024/11/20 United States Zenocutuzumab anti-HER3/HER2 bispecific antibody 2024/12/4 United States

Several methodological and technological trends underpin the 2024 cohort of FIC approvals. First, biologic modality innovation emerged as a defining feature, with half of the approved therapies utilizing nontraditional formats. These include bispecific antibodies (e.g., tarlatamab, zenocutuzumab, and ivonescimab), engineered cytokines (e.g., nogapendekin alfa inbakicept), and adoptive cell therapies (e.g., lifileucel and afamily gene autoleucel). These formats allow for the selective engagement of immune pathways, dual targeting of tumor resistance mechanisms, and expansion of therapeutic reach to previously “undruggable” targets. Second, target selection strategies have increasingly focused on lineage-restricted or tumor-specific antigens—such as CLDN18.2, DLL3, and MAGE-A4—enabling greater precision with minimized off-target toxicity. The approval of revumenib also exemplifies the power of structure-guided drug design against epigenetic regulators with defined molecular subtypes. Third, clinical development has leveraged biomarker-enriched or tissue-agnostic trial designs, including basket trials for BRAF or NRG1 fusions and immunotherapy trials focused on resistant disease subsets. These adaptive strategies accelerated development timelines and enabled efficient validation in genomically defined populations. Together, these shared features reflect a broader evolution in oncology R&D—away from empirical screening and toward a paradigm anchored in mechanism-driven, biomarker-enabled, and platform-empowered strategies. 65 Below, we highlight selected agents from this cohort to examine how these principles have translated into clinically meaningful first-in-class innovations.

Zolbetuximab, approved in Japan in March 2024, is the first monoclonal antibody directed against CLDN18.2, a tight junction protein aberrantly expressed in gastric and gastroesophageal cancers. 66 In the phase III SPOTLIGHT trial, 67 zolbetuximab extended median progression-free survival (PFS) by 2 months (10.6 vs. 8.7 months; hazard ratio (HR) 0.75) and improved overall survival (OS) by 3 months (18.2 vs. 15.5 months; HR 0.75) compared with chemotherapy alone. Further evidence from the phase III GLOW trial 68 reinforced these findings, with a PFS improvement of 1.4 months and OS gain of more than 2 months. Unlike traditional surface receptors or growth factor pathways, tight junction proteins like CLDN18.2 are accessible on the tumor cell surface while remaining largely restricted from normal tissues, minimizing off-target toxicity and enhancing tumor specificity. 69 Zolbetuximab is the first successful therapeutic target of this protein class. Encouraged by results in gastric cancer, ongoing trials are exploring its utility in pancreatic, biliary, and esophageal cancers. 70 – 72

Nogapendekin alfa inbakicept, approved by the FDA in April 2024, 73 , 74 is the first therapy to target the interleukin-15 receptor (IL-15R) pathway. As an IL-15 superagonist fusion protein, this drug selectively activates CD8⁺ T cells and natural killer (NK) cells without significantly expanding regulatory T cells—amplifying cytotoxic immunity while minimizing immunosuppressive feedback. 75 Its clinical efficacy was demonstrated in the pivotal QUILT-3.032 trial, 76 where its intravesical administration in combination with Bacillus Calmette–Guérin (BCG) achieved a complete response rate of 62% (95% CI: 51–73) in patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ. Among responders, 58% maintained remission for at least 12 months, and 40% sustained responses for at least 24 months. 74 This bladder-sparing immunotherapy offers a clinically meaningful alternative to radical cystectomy for BCG-unresponsive NMIBC. As the first-in-class cytokine receptor agonist of its class, it introduces a new paradigm for localized immune-based treatment in early-stage disease.

Tarlatamab, approved by the US FDA in May 2024, represents the first BiTE to gain regulatory approval for a solid tumor. 77 This study also represents the first clinical validation of DLL3, a lineage-specific Notch ligand highly expressed in small cell lung cancer (ES-SCLC), as a therapeutic target. 78 Tarlatamab employs a dual-binding mechanism that links DLL3 on tumor cells with CD3 on T cells, redirecting cytotoxic T cells to selectively attack DLL3-expressing cancer cells. The pivotal DeLLphi-301 trial 79 demonstrated an ORR of 40%, with 30% of patients maintaining responses for at least 9 months—a significant achievement in a disease setting historically resistant to immunotherapy. Although cytokine release syndrome (CRS) and neurotoxicity remain relevant safety concerns, its approval has established a precedent for BiTE-based strategies in solid tumors. More broadly, it highlights the potential of T-cell redirection to overcome immune exclusion in “cold” tumors such as SCLC, enabling robust immune infiltration and potent antitumor activity.

Ivonescimab, approved by the NMPA in May 2024, represents a novel bispecific antibody that targets both PD-1 and VEGF-A. By blocking immune checkpoint signaling and tumor angiogenesis, ivonescimab synergistically integrates T-cell reinvigoration with vascular normalization—two previously distinct therapeutic strategies. 80 Unlike conventional monotherapies, its dual-targeting design modulates immune suppression and disrupts the tumor microenvironment, which fosters immune exclusion. In a phase II trial, ivonescimab in combination with chemotherapy yielded a notable ORR in NSCLC, particularly among patients with limited prior treatment options. 81 This approval marks an important milestone in the evolution of bispecific biologics for solid tumors, broadening the clinical utility of T-cell–modulating agents beyond hematologic malignancies.

Afamitresgene autoleucel is the first TCR-based cell therapy 82 approved by the FDA in August 2024 for the treatment of MAGE-A4-positive advanced or metastatic synovial sarcoma. 83 It leverages TCR engineering to equip a patient’s own T cells with specificity for the MAGE-A4 antigen, which is overexpressed in synovial sarcoma and other solid tumors. In a pivotal single-arm trial, afamitresgene autoleucel achieved a promising ORR of 43.2%, with a median duration of response of 6 months. Given the absence of effective targeted therapies and the aggressive nature of the disease, Afami-cel has received accelerated approval based on its robust response rates in this hard-to-treat population. Unlike CAR-T-cell therapies, which are limited to surface antigens, TCR-T-cell therapies recognize tumor-specific intracellular antigens presented via MHC complexes, allowing for the targeting of oncogenic drivers that are inaccessible to conventional antibody- or CAR-based approaches. By overcoming the limitation of surface antigen dependency, TCR-T cells broaden the scope of adoptive cell therapy to include solid tumors with low or absent surface marker expression. 84 , 85

Revumenib, approved by the FDA in November 2024, is a groundbreaking oral menin inhibitor developed for acute leukemias harboring lysine methyltransferase 2 A rearrangements (KMT2A-r). 86 Its mechanism of action disrupts the interaction between menin and MLL1 proteins, a critical driver of leukemogenesis in these genetically defined subtypes. Revumenib demonstrated complete remission (CR) plus CR with partial hematologic recovery (CRh) of 21.2% in the pivotal AUGMENT-101 trial, enabling a subset of patients to proceed with curative stem cell transplantation—a key outcome for potential long-term survival. 86 , 87 Given the poor prognosis and chemoresistance of KMT2A-r and NPM1-m leukemias, revumenib addresses a critical unmet need. Ongoing studies are investigating combination regimens to mitigate emerging resistance mutations and extend the durability of the response.

Zenocutuzumab is a bispecific antibody that targets HER2 and HER3 receptors for the treatment of advanced or metastatic NSCLC and pancreatic adenocarcinoma harboring NRG1 fusions. Although rare, NRG1 fusions are potent oncogenic drivers with limited treatment options. 88 By simultaneously binding to the extracellular domains of HER2 and HER3, zenocutuzumab disrupts receptor dimerization and NRG1-mediated signaling—effectively blocking downstream oncogenic pathways and overcoming resistance mechanisms associated with HER family monotherapies. In the pivotal eNRGy trial, zenocutuzumab achieved an ORR of 33%, with a median response duration of 7.4 months in NSCLC patients, and an ORR of 40% in pancreatic cancer patients, with durable responses of up to 16.6 months. 89

In summary, the year 2024 featured a notably diverse portfolio of FIC oncology drug approvals. These breakthroughs underscore how mechanistic diversity, tumor-specific antigen targeting, and advanced biologic platforms—whether acting independently or synergistically—are shaping the next wave of cancer treatment.

Landscape of potential FIC products in development

To capture the evolving landscape of investigational FIC oncology drugs and anticipate future trends, we analyzed the pipeline of PFIC candidates. Consistent with previous definitions, 19 , 28 , 44 PFIC drugs are defined as investigational agents that target previously undrugged biological targets or employ novel mechanisms of action and represent the leading drugs within their class. From 2009 to 2024, we identified a total of 1,578 PFIC oncology drugs that have entered and remained in clinical development. These candidates span all trial stages: 22 agents at the Investigational New Drugs (IND) stage, 725 in Phase I, 724 in Phase II, 100 in Phase III and 7 under New Drug Applications (NDA) at the end of 2024. The number of PFIC drugs entering the clinical phase each year increased over this period ( p < 0.001), with an average annual growth rate of 43.6% (Fig. 2a ).

Analysis of innovation archetypes revealed a marked shift in focus compared with approved FIC drugs (Fig. 2c ). In the approved FIC cohort, new targets accounted for 55.9%, whereas in the PFIC cohort, their share declined to 36.0% (568/1578). In contrast, new modalities or mechanisms rose from 28.0% in the approved cohort to 58.0% (916/1578) in the PFIC pipeline. This trend reflects a growing adoption of advanced therapeutic platforms, such as cell therapies, ADCs, and bispecific antibodies. These modalities enhance precision and therapeutic indices, often by re-engaging established targets through innovative formats. The share of multitarget strategies has declined—from 15.1% in the approved FIC group to 5.5% (87/1578) in the current PFIC pipeline when categorized by primary innovation archetype. However, this apparent decrease does not indicate diminished interest in multitarget approaches. Instead, it largely reflects the categorization logic of our framework: when a drug incorporates multiple targets alongside a novel modality (e.g., bispecific antibody) or engages previously unexploited targets, it is assigned to those dominant innovation types rather than the multitarget category. As such, many agents employing multitarget mechanisms are already subsumed under “new modality” or “new target” classes. Indeed, an additional 499 PFIC candidates classified primarily as novel molecules or those that use new modalities also incorporate multiple functional components, such as dual-antigen engagement, pathway coinhibition, or immune–stromal cotargeting. This underscores the continued and evolving relevance of multitarget strategies as a means of overcoming tumor heterogeneity, bypassing resistance circuits, and enhancing therapeutic durability, even as their classification becomes entangled with other innovation attributes. 90 , 91

While the pipeline of PFIC drugs continues to expand, the path from clinical development to market approval remains arduous. Over the past decade, the overall probability of success from Phase I to market approval has shown a declining trend—ranging between 7.5% to 16.4%, with an average of approximately 10%. 92 – 94 Estimated transition rates have remained sobering: 46–64% from Phase I to Phase II, 24–33% from Phase II to Phase III, 55–61% from Phase III to the NDA or Biologics License Application (BLA) submission, and 85–92% for final regulatory approval. These figures have remained largely unchanged despite technological advances. Notably, cancer therapeutics continue to exhibit some of the lowest clinical success rates across all therapeutic areas owing to the biological heterogeneity, target redundancy, and translational uncertainties that typify oncologic diseases. 95

On the basis of these transition probabilities and the current distribution of PFIC drug candidates across clinical stages, we estimated that ~200–300 of these PFIC candidates may ultimately achieve FIC approval over the next decade—exceeding the 93 FICs recorded from 2009 to 2024. Although such projections appear optimistic, they are likely to overstate the number of PFIC candidates that will ultimately succeed, as FIC development remains fraught with scientific, technological, and regulatory hurdles. 18 , 96 These hurdles disproportionately affect first-in-class candidates, which by definition lack prior clinical precedent and often navigate uncharted mechanistic territory. A salient illustration is the case of imatinib, the first BCR-ABL inhibitor for CML. Although the BCR-ABL fusion gene was discovered as a driver mutation in 1984, 97 nearly two decades of translational effort took place before imatinib gained FDA approval in 2001. 98 This example underscores the long gestation periods required to translate fundamental discoveries into approved therapies. Thus, while the expanding PFIC pipeline signals intensified global innovation efforts, volume alone does not guarantee clinical or regulatory success. For first-in-class therapies in particular, this gap between discovery and approval serves as a reminder that pioneering innovation often entails high risk and high failure rates. Nonetheless, such exploratory endeavors are indispensable, as they transform scientific curiosity into therapeutic possibilities and lay the foundation for transformative advances in patient care.

Molecular targets and signaling pathways

The engine of FIC innovation lies in the precise dissection of cancer biology—specifically, the identification of molecular targets that are biologically essential, pharmacologically tractable and clinically actionable. These targets function as critical nodes within oncogenic signaling networks, regulating tumor initiation, metastasis, immune escape, angiogenesis, and crosstalk between malignant cells and the tumor microenvironment. 99 Therapeutic innovation is not merely about identifying new proteins; it is about understanding how perturbing specific pathways can reshape disease trajectories. 100 This section examines the evolving logic of target selection and mechanism-based therapy design. We begin by revisiting well-established targets in FIC treatment paradigms and then explore emerging targets populating the PFIC pipeline. Finally, we highlight breakthroughs in historically undruggable targets, where advances in structural biology, chemical design, and platform technologies are rewriting the rules of druggability.

Approved targets and their pathways

Anticancer therapies are typically classified into three main therapeutic categories: cytotoxic drugs, targeted small-molecule drugs, and targeted biologics. To better capture the breadth of therapeutic innovation, these categories are further subdivided by molecular class and mechanistic action, following a hierarchical classification framework (Fig. 4 ). 19 , 21 , 28 In our dataset, all approved FIC approvals fall into two target categories: small-molecule drugs (48, 51.6%) and targeted biologics (45, 48.4%), with none representing classical cytotoxic agents. This complete absence of chemotherapies highlights a decisive shift in innovation priorities. The pattern mirrors broader oncology drug approval trends—only 8.7% of oncology indications approved in the US between 2000 and 2022 were cytotoxic agents, 21 , 101 and the European Medicines Agency (EMA) has not approved a new first-in-class cytotoxic agent since 2016. 102 More than a categorical change, this transition signifies a growing emphasis on selectively disrupting tumor-intrinsic signaling, reprogramming immune responses, and remodeling the tumor microenvironment—mechanistic strategies that enhance tumor specificity and reduce systemic toxicity. Fig. 4 Classification of approved FICs on the basis of their mechanism of action from 2009 to 2024. Targeted biologics include cytotoxic agents, bispecific constructs, antibodies, cell and gene therapies, immune checkpoint inhibitors, and oncolytic approaches. Small-molecule drugs are dominated by kinase inhibitors, with additional classes such as epigenetic modulators, transcription factor inhibitors, apoptosis restorers, and pathway-specific agents

Within the category of targeted small-molecule drugs, kinase inhibitors constitute the largest class, representing 70.8% of all FIC approvals. Their dominance is rooted in the centrality of kinase signaling in cancer progression and the structural “druggability” of kinases, which enables the design of adenosine triphosphate (ATP)-competitive or allosteric inhibitors with high selectivity. 103 Landmark developments targeting EGFR, ALK, BRAF, RET, and cellular mesenchymal‒epithelial transition factor (c-MET) have transformed the treatment landscape in lung 104 and melanoma 105 and will continue to serve as paradigms of precision-guided therapy. In addition to kinases, epigenetic modifiers have emerged as the second-largest class, comprising 10.4% of targeted chemical drugs. These therapies target enzymatic regulators of DNA methylation (e.g., DNA methyltransferases, DNMTs), histone modification (e.g., enhancer of zeste homolog 2, EZH2, histone deacetylases, HDACs), and metabolic reprogramming (e.g., IDH1/2)—mechanisms that are often dysregulated in cancer but reversible, offering therapeutic windows even in tumors lacking canonical oncogenic mutations. 106 – 108 Representative agents such as tazemetostat (EZH2 inhibitor), ivosidenib (IDH1 inhibitor), and enasidenib (IDH2 inhibitor) have demonstrated clinical efficacy, particularly in hematologic malignancies and select solid tumors, where clonal evolution and epigenetic plasticity drive disease persistence. 109 – 111

In addition to kinase inhibitors and epigenetic regulators, a mechanistically diverse subset of small-molecule FIC therapies—although representing a smaller share of approvals—demonstrates the field’s expanding capacity to target previously underexploited oncogenic processes. These agents intervene in key biological vulnerabilities beyond canonical signaling or chromatin regulation. For example, hormonal signaling modulators such as antiandrogens (e.g., abiraterone) and estrogen receptor antagonists disrupt endocrine-driven tumor growth, particularly in prostate and breast cancers. 112 Apoptosis reactivators, including BCL-2 inhibitors such as venetoclax, 46 restore programmed cell death in malignancies that evade intrinsic apoptotic cues. Therapies targeting developmental pathways, such as Hedgehog inhibitors (e.g., vismodegib 113 ), act on embryonic signaling circuits aberrantly reactivated in adult tumors. DNA damage response modulators, exemplified by PARP inhibitors like olaparib, 114 exploit synthetic lethality in tumors harboring BRCA mutations or homologous recombination deficiencies. Other compounds, such as nuclear export inhibitors (e.g., selinexor 115 ), reinstate the nuclear retention of tumor suppressor proteins, counteracting oncogenic transcriptional escape. Finally, the emergence of transcriptional and metabolic regulators, although early in their clinical journey, offers promising avenues for reshaping gene expression and energy metabolism in cancer cells.

Within the category of targeted biologics, the most prevalent subcategory comprises targeted cytotoxic agents, which account for 33.3% of all biologic FIC approvals. Among these, ADCs constitute the majority (73.3%). By coupling tumor-targeting specificity with the potent cell-killing capacity of cytotoxic payloads, ADCs enhance therapeutic precision and reduce systemic toxicity, positioning them as a next-generation evolution of traditional cytotoxic therapy. 116 In parallel, immunotoxins such as moxetumomab pasudotox (anti-CD22) and tagraxofusp (anti-CD123) employ a similar logic of targeted lethality through toxin-based moieties, further expanding the repertoire of precision cytotoxicity. The second-largest subclass of targeted biologics consists of bispecific constructs, accounting for 20% of FIC approvals. These agents are designed to simultaneously bind two distinct molecular targets—most commonly a tumor-associated antigen and an immune effector receptor—thereby bridging tumor cells with immune effectors to potentiate targeted immune activation. For example, CD20/CD3 bispecific antibodies such as mosunetuzumab 117 redirect cytotoxic T cells to B-cell malignancies, enabling potent antitumor responses independent of the conventional antigen presentation pathway.

Another subclass of targeted biologics is antitumor-associated antigen (TAA) antibodies, accounting for 13.3% of approvals. These agents function by recognizing proteins aberrantly overexpressed on the surface of malignant cells, thereby enhancing immune-mediated clearance through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) or complement activation. 118 Clinically validated examples include daratumumab, which targets CD38 in multiple myeloma; dinutuximab, which targets disialoganglioside GD2 (GD2) in neuroblastoma; and zolbetuximab, which is directed at CLDN18.2 in gastric and gastroesophageal cancers—each demonstrating how surface antigen specificity can be harnessed for selective tumor targeting across distinct cancer types. Autologous cell therapies, particularly CAR-T cell therapies, constitute another 13.3% of biologic FIC approvals. These engineered T cells, which are designed to recognize tumor antigens independently of human leukocyte antigen (HLA) presentation, mark a paradigm shift toward living, patient-derived therapeutics. ICIs represent another 8.9% of targeted biologics. By blocking regulatory pathways such as PD-1/PD-L1 and CTLA-4, ICIs reinvigorate exhausted T cells and restore antitumor immunity. 119 Their broad efficacy across tumor types with high mutational burdens or immune infiltration underscores the power of modulating immune surveillance as a therapeutic strategy. Each of the remaining targeted biologics accounts for 2–3%, including monoclonal antibodies against cytokines and receptors, antiangiogenic agents such as anti-VEG(F)R constructs, gene therapies, and immunostimulants. Although smaller in proportion, these therapies exemplify the expanding reach of biologics into novel molecular mechanisms and previously untapped vulnerabilities within the tumor and its microenvironment.

Mapping the molecular landscape of approved FIC therapies reveals that innovation is converging across nearly all hallmarks of cancer (Fig. 5 ). To sustain proliferative signaling, growth factor receptors and receptor tyrosine kinases (RTKs), including EGFR, FGFR, VEGFR, and PDGFR, together with downstream pathways such as the PI3K/AKT and MAPK pathways, remain dominant therapeutic targets that orchestrate oncogenic proliferation and survival. 120 To evade immune destruction, ICIs against PD-1, PD-L1, CTLA-4, and LAG-3 restore T-cell cytotoxicity by releasing inhibitory brakes, whereas bispecific antibodies further expand immunotherapy modalities, achieving durable responses in previously intractable tumors. 121 To resist cell death, therapies target apoptosis regulators, including BCL-2, Hsp90, XPO1, and EZH2, as well as proapoptotic mediators, such as TRAIL, thereby reinstating programmed cell death and proving particularly effective in hematologic malignancies and refractory solid tumors. 122 To maintain genome stability, inhibitors of cyclin-dependent kinase 4/6 (CDK4/6), PARP, and topoisomerases disrupt DNA repair and replication in genetically unstable cancers, with synthetic lethality strategies (e.g., PARP inhibitors in BRCA-mutated tumors) exemplifying tumor-specific vulnerabilities. 123 Tumor-promoting inflammation is countered by therapies targeting CSF1R, GM-CSF, and the hypoxia-inducible factor HIF-2α, which modulate immune-suppressive niches and hypoxia-driven resistance. 124 To prevent invasion and metastasis, adhesion and cytoskeletal targets such as CLDN18.2, Nectin-4, and microtubules have emerged as actionable druggable nodes. 125 Fig. 5 Mapping first-in-class therapeutics to cancer hallmarks. Cancer hallmarks are shown around the central tumor cell, with corresponding therapeutic strategies and drug classes annotated. Representative drug classes include kinase inhibitors, hormonal therapies, transcription factor inhibitors, PARP inhibitors, topoisomerase inhibitors, antibody–drug conjugates, bispecific antibodies, epigenetic regulators, senolytic targets, and microbiome-targeted strategies, each of which are associated with specific cancer hallmarks, such as resistance to cell death, genome instability, angiogenesis, invasion and metastasis, immune evasion, and cellular metabolism deregulation. ICI: immune checkpoint inhibitor, CSF1R: colony-stimulating factor 1 receptor, PARP: poly (ADP-ribose) polymerase, IDH: isocitrate dehydrogenase, EZH2: enhancer of zeste homolog 2, BET: bromodomain and extraterminal motif protein, BRD4: bromodomain-containing protein 4, BCL-2: B-cell lymphoma 2, Hsp90: heat shock protein 90, mAb: monoclonal antibody, VEGF(R): vascular endothelial growth factor (receptor), HDAC: histone deacetylase. This figure was created at https://BioRender.com

Beyond classical hallmarks, modern FIC therapies also target epigenetic plasticity via BET and BRD4 degraders or HDAC inhibitors and address tumor heterogeneity through multitarget combinations, including bispecific antibodies. Emerging senolytic agents further eliminate therapy-induced senescent cells. Collectively, these strategies underscore a shift toward mechanism-driven intervention, whereby FIC drug classes systematically map onto the biological circuits of malignancy—spanning proliferation, immune escape, apoptosis resistance, genomic instability, angiogenesis and metastatic spread.

Novel targets for PFIC drugs

Among the 1578 PFIC drugs, 569 (36.0%) are defined as novel targets, which also represent the most rapidly advancing candidates within their category. This observation highlights the continuous expansion and diversification of therapeutic strategies in oncology. The top most actively pursued targets in the PFIC pipeline include 4-1BB (0.8%), IL-15 (0.8%), mucin 1 (MUC1) (0.7%), CD70 (0.6%), CD276 (0.6%), CD28 (0.6%), CD47 (0.6%), mesothelin (MSLN) (0.6%), and HER3 (0.5%) (Table 3 ). These molecules are associated with major hallmarks, such as avoiding immune destruction (4-1BB, IL-15, CD28, and TIGIT), immune evasion and cell–cell interactions (CD47, CD70, and CD276), and sustaining proliferative signaling (HER3 and MUC1). Additional highly investigated targets, including C-type lectin-like molecule-1 (CLL-1), claudin-6 (CLDN6), transforming growth factor-beta receptor 2 (TGFBR2), glypican-3 (GPC3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), Wilms tumor 1 (WT1), and the viral oncogene HPV E6/E7, further extend the PFIC pipeline toward hallmarks of genome instability, invasion and metastasis, and tumor-promoting inflammation. Table 3 Top emerging targets by the number of investigational potential first-in-class drugs Targets Number of investigational drugs 4-1BB 12 Interleukin 15 (IL-15) 12 Mucin 1 (Muc1) 11 CD27 ligand (CD27L, CD70) 9 CD276 (B7-H3) 9 Cluster of differentiation 28 (CD28) 9 Cluster of differentiation 47 (CD47) 9 Mesothelin (MSLN) 9 Human epidermal growth factor receptor 3 (HER3) 8 C-type lectin-like molecule-1 (CLL-1) 7 Claudin-6 (CLDN6) 7 Transforming growth factor beta receptor type 2 (TGFBR2) 7 Glypican-3 (GPC3) 6 T-cell immunoreceptor with Ig and ITIM domains (TIGIT) 6 Wilms tumor protein 1 (WT1) 6 Delta like ligand 3 (DLL3) 5 Fibroblast activation protein (FAP) 5 G1 to S phase transition 1(GSPT1) 5 Interleukin 10 (IL-10) 5 Receptor tyrosine kinase-like orphan receptor 1 (ROR1) 5 Stimulator of interferon genes (STING) 5 Human Papillomavirus E6 and E7(HPV E6 and HPV E7) 5

The growing emphasis on these novel drug targets indicates a diversification of therapeutic approaches beyond established pathways such as PD-1/PD-L1 and HER2. Many of these targets play crucial roles in immune modulation, tumor microenvironment interactions, and cancer-specific antigen recognition, providing fertile ground for next-generation treatments. For example, costimulatory and immune-modulatory molecules, including 4-1BB (CD137), CD27/CD70, CD28, and CD47, regulate T-cell activation and immune response modulation. 4-1BB agonists enhance T-cell proliferation and memory formation, 126 while CD47 inhibitors block the “do not eat me” signal, thereby preventing tumor immune evasion. 127 Tumor-specific antigens such as CD276, MSLN, MUC1, and GPC3 are highly expressed in various solid tumors but remain highly expressed in normal tissues, making them ideal targets for ADCs and CAR-T cell therapies. 128 , 129 Moreover, claudins and cell adhesion targets such as CLDN6, which are upregulated in gastric, pancreatic, and ovarian cancers, have drawn increasing interest for targeted therapies. 130 – 133 In the context of cytokines and receptors, IL-15 enhances natural killer (NK) and T-cell functions, 134 while TGFBR2 plays a role in tumor immune suppression, making both attractive targets for immune-boosting treatments. 135 Virus-associated targets, such as HPV E6/E7, are key drivers of cervical, head and neck cancers, supporting the development of therapeutic vaccines and T-cell therapies. 130 , 136 Finally, neuroendocrine and peptide receptors, including somatostatin receptor type 2 (SSTR2) and gastrin-releasing peptide receptor (GRPR), are overexpressed in neuroendocrine tumors, paving the way for peptide-based radioligand therapies. 131 The growing focus on these novel targets signals a shift toward more precise and tumor-specific treatment approaches, particularly in immuno-oncology, tumor metabolism, and antibody-based therapeutics, offering new hope for patients whose treatment options are limited.

Breakthroughs in previously undruggable targets

The pursuit of FIC drugs has driven innovation in drug discovery, particularly in pushing the boundaries of what is considered “undruggable”. Historically, many oncogenic proteins eluded conventional drug discovery, often owing to structural constraints, a lack of defined binding pockets, and intrinsically disordered regions that preclude effective ligand engagement. Recent advances in medicinal chemistry, structural biology, and computational modeling—alongside the emergence of novel strategies such as covalent inhibitors, allosteric modulators, targeted protein degradation (PROTACs), and synthetic lethality—have collectively overcome longstanding challenges and engage previously intractable oncogenic drivers. These modality-driven breakthroughs have shifted several once-elusive proteins from theoretical interest to clinical translation. In the following sections, we highlight several illustrative examples—KRAS, tumor protein p53 (p53), bromodomain-containing protein 4 (BRD4), B-cell lymphoma-extra large (Bcl-xL) and myelocytomatosis (MYC)—that have transitioned from longstanding scientific challenges to clinically actionable targets through distinct modality innovations, followed by a brief overview of emerging undruggable targets now entering translational development.

KRAS

KRAS, a canonical oncogene within the RAS family, has long been considered undruggable because of its smooth surface, lack of deep binding pockets, and high affinity for guanosine-5’-triphosphate (GTP)/guanosine-5’-diphosphate (GDP), which makes traditional small-molecule inhibitors ineffective. Among its mutations, KRAS G12C is a prevalent driver in NSCLC but has remained clinically intractable for decades. 137 A major breakthrough came with the development of covalent inhibitors that irreversibly bind to the mutant cysteine residue unique to the KRAS G12C mutant, exploiting a transient pocket in its inactive, GDP-bound state. This led to the approval of the first-in-class KRAS G12C inhibitor sotorasib (AMG 510) in 2021 for the treatment of NSCLC. 132 Subsequently, adagrasib (MRTX849) was approved, offering an alternative with a longer half-life and enhanced central nervous system (CNS) penetration. 133 While these approvals marked a turning point in RAS-targeted therapy, clinical responses remain heterogeneous. Many patients exhibit only partial responses, and most eventually develop resistance due to secondary KRAS mutations (e.g., Y96D), bypass signaling via EGFR or FGFR, or histological transformation. These findings have sparked a wave of combination trials, including the use of KRAS G12C inhibitors with Src homology 2 domain-containing phosphatase-2 (SHP2), mitogen-activated extracellular signal-regulated kinase (MEK), EGFR inhibitors, or immune checkpoint inhibitors, aimed at overcoming adaptive resistance and improving durability.

Building on these advances, next-generation strategies are now targeting a broader spectrum of KRAS alterations, including G12D, G12V, and Q61 mutations. For example, MRTX1133, a selective G12D inhibitor, has shown promising preclinical activity and is currently in early-phase clinical trials. Other approaches under development include pan-KRAS inhibitors, which aim to suppress multiple KRAS alleles simultaneously, and PROTAC-based degraders, which bypass the need for traditional pocket binding by coopting the ubiquitin‒proteasome system to eliminate the KRAS protein entirely. 138

p53

p53, one of the most frequently mutated genes in human cancers, functions as a central tumor suppressor by orchestrating DNA damage responses, cell cycle arrest, and apoptosis. Over 50% of human tumors harbor p53 pathway alterations, making it one of the most compelling yet historically elusive therapeutic targets. 139 The complexity of p53 targeting arises from two major challenges: (1) its structurally diverse and often disordered conformations, especially in mutant forms, and (2) its tight regulation by negative regulators such as mouse double minute 2 (MDM2), which degrades wild-type p53 via the ubiquitin‒proteasome system. The first breakthrough came with APR-246 (eprenetapopt), a small molecule that covalently binds mutant p53, restoring its wild-type conformation and transcriptional activity. This agent has demonstrated encouraging activity in treating hematologic malignancies, particularly p53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and has advanced into pivotal clinical trials. However, later-phase trials revealed variable efficacy, highlighting the need for next-generation reactivators with increased selectivity and stability.

Recent advances have introduced more refined reactivation strategies. For example, PC14586 (rezatapopt), a small molecule currently in clinical development, selectively targets the Y220C mutant p53, stabilizing a transient surface pocket unique to this hotspot mutation. Similarly, stapled or stabilized α-helical p53 peptides mimic the transactivation domain of p53 and block MDM2/p53 interactions, offering high specificity with improved pharmacokinetics. 140 In parallel, MDM2 inhibitors such as idasanutlin 141 and navtemadlin 142 have emerged as promising tools to restore wild-type p53 function by preventing its degradation. These agents show particular potential for treating TP53 wild-type tumors, especially hematologic malignancies. However, toxicity and dose-limiting thrombocytopenia remain clinical hurdles, prompting the exploration of intermittent dosing and combination strategies. 143 Finally, synthetic lethality offers an indirect route to exploit p53 deficiency. In p53-deficient tumors, cells rely heavily on parallel survival pathways, such as ATR- or WEE1-mediated DNA damage checkpoints. 144 Inhibitors of these proteins selectively kill p53-deficient cells, and several such combinations are under active clinical evaluation. 145 The identification of context-dependent synthetic lethal partners for p53-mutant cancers remains a rich area for FIC development.

BRD4

BRD4, a member of the bromodomain and extraterminal (BET) protein family, is a pivotal epigenetic regulator that links histone acetylation to transcriptional activation. 146 By recognizing acetylated lysine residues on histones, BRD4 facilitates the recruitment of the transcriptional machinery to super-enhancers and promotes the expression of key oncogenes, notably MYC. BRD4 was historically viewed as undruggable owing to the shallow and conserved nature of its bromodomain pockets, which complicated the development of selective inhibitors. The first breakthrough came with the discovery of BET inhibitors such as JQ1, which competitively bind to the bromodomains of BRD4 and displace it from chromatin. 147 This disrupted the expression of oncogenic transcriptional programs and demonstrated significant preclinical activity, especially in hematologic malignancies and (nuclear protein in the testis) NUT midline carcinoma. Clinical derivatives such as OTX015 and CPI-0610 entered trials soon thereafter. 148 , 149 However, early clinical studies revealed several limitations of BET inhibitors: modest single-agent activity, rapid development of resistance, and dose-limiting toxicities, including thrombocytopenia and gastrointestinal side effects. These challenges underscore the need for more potent and selective BRD4-targeting strategies. 150 , 151

A major conceptual leap has been achieved with the advent of targeted protein degradation technologies, particularly proteolysis-targeting chimeras (PROTACs). 152 BRD4 degraders such as ARV-825 and dBET1 function by tethering BRD4 to an E3 ubiquitin ligase (e.g., cereblon (CRBN) or von hippel‒lindau (VHL)), leading to its ubiquitination and subsequent degradation via the proteasome. 153 , 154 This catalytic mechanism achieves more sustained and profound suppression of BRD4 than does occupancy-based inhibition. Compared with BET inhibitors, BRD4 degraders have demonstrated superior efficacy in preclinical models, including those resistant to conventional BET inhibitors, and are now progressing through early-phase clinical trials. Additionally, combination strategies are being actively pursued to increase therapeutic durability and minimize resistance. These include pairing BRD4 degraders or inhibitors with kinase inhibitors (e.g., PI3K, cyclin-dependent kinase 7 (CDK7)), immune checkpoint inhibitors, and other epigenetic modulators. The integration of BRD4 targeting into synthetic lethal frameworks—such as cotargeting BRD4 and myeloid cell leukemia-1 (MCL-1) in AML—also offers promising directions for future FIC development. Together, the trajectory of BRD4-targeted therapy exemplifies how mechanistic innovation—from bromodomain antagonism to protein degradation—has expanded the therapeutic toolkit against transcriptional addiction in cancer. 155

Bcl-xL

Bcl-xL, an antiapoptotic member of the Bcl-2 protein family, plays a critical role in maintaining mitochondrial membrane integrity and suppressing programmed cell death. 156 While its overexpression contributes to therapy resistance and tumor survival across various malignancies, Bcl-xL also performs essential homeostatic functions in platelets and other normal tissues. 157 This duality has historically rendered Bcl-xL “undruggable,” as pharmacologic inhibition often results in dose-limiting thrombocytopenia and on-target toxicity. 158 Early drug discovery efforts focused on pan-Bcl-2 inhibitors or dual Bcl-2/Bcl-xL inhibitors, such as navitoclax (ABT-263), which have shown potent proapoptotic activity in preclinical models and early clinical trials, especially in hematologic malignancies. 122 , 159 However, the clinical utility of navitoclax is significantly constrained by its pronounced platelet toxicity—a direct consequence of Bcl-xL inhibition in megakaryocytes and circulating platelets. 160 This toxicity-limiting ceiling highlights the need for more selective or context-specific strategies.

Recent advances have introduced next-generation Bcl-xL-targeting approaches that aim to preserve antitumor efficacy while minimizing systemic toxicity. A major improvement has been achieved with the application of targeted protein degradation technologies. PROTAC-based Bcl-xL degraders, such as DT2216, exploit the selective expression of E3 ligases in tumor versus normal cells. 161 For example, DT2216 recruits the VHL E3 ligase, which is expressed at low levels in platelets, thereby enabling the selective degradation of Bcl-xL in tumor cells while sparing platelet populations. This modality-driven selectivity has demonstrated favorable preclinical profiles and is currently advancing through early-phase clinical trials. Moreover, combination therapies targeting parallel survival pathways are being actively pursued to increase treatment efficacy and overcome resistance. Examples include cotargeting Bcl-xL and MCL-1 to synergistically induce apoptosis in resistant leukemias 162 or pairing Bcl-xL modulators with immune checkpoint inhibitors to increase tumor immunogenicity. These strategies reflect a shift from direct inhibition to systems-level modulation of the apoptotic machinery. 163

MYC

MYC is a master transcription factor that regulates genes involved in cell proliferation, metabolism, and survival. Aberrant MYC activation—via gene amplification, chromosomal translocation, or upstream signaling—occurs in more than 50% of human cancers, making it one of the most pervasive oncogenic drivers. However, its intrinsically disordered structure, absence of conventional ligand-binding pockets, and widespread physiological roles have historically rendered MYC “undruggable”. 164 Recent advances have catalyzed a paradigm shift in MYC-targeted drug discovery. One of the most promising direct inhibition strategies is Omomyc, a dominant-negative MYC mimic that disrupts MYC–MAX dimerization and thereby impairs MYC-driven transcriptional programs. 165 Originally developed as a research tool, Omomyc has now transitioned into the clinic as OMO-103, a recombinant miniprotein currently in phase I/II trials for advanced solid tumors, including NSCLC and SCLC. Preliminary results have shown encouraging safety and signs of tumor stabilization, validating the concept of direct MYC targeting in patients.

In parallel, indirect strategies have emerged that exploit MYC-driven dependencies. 166 Synthetic lethality approaches leverage the observation that MYC-overexpressing tumors are particularly reliant on specific parallel pathways. 167 For example, inhibitors of protein arginine methyltransferase 5 (PRMT5), PIM kinases, and cyclin-dependent kinase 9 (CDK9) can preferentially kill MYC-driven cancer cells by disrupting transcriptional elongation or RNA processing. Several such agents are undergoing early-phase clinical testing. In addition to inhibition, targeted degradation offers a complementary route. PROTACs and molecular glue degraders are being designed to hijack the ubiquitin–proteasome system and induce selective MYC elimination, although these remain largely in the preclinical phase owing to challenges in ligand design. 168 Moreover, RNA-targeting strategies such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) have also been explored to suppress MYC mRNA expression, some of which have demonstrated promising activity in MYC-addicted models of neuroblastoma and triple-negative breast cancer (TNBC). 169 , 170

Emerging undruggable targets

Beyond the well-established examples discussed above, a growing number of historically intractable proteins are now advancing into preclinical and early clinical development, further extending the reach of first-in-class innovation. β-catenin, a central effector of Wingless-related integration site (Wnt) signaling long deemed undruggable owing to its shallow surface and structural flexibility, is now being targeted via inhibitors of its interaction with CREB-binding protein (CBP), as well as through targeted degradation strategies. 171 Similarly, the transcriptional coactivators yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ)—critical downstream mediators of the Hippo pathway—are gaining traction as drug targets through emerging peptide disruptors and small-molecule inhibitors designed to interfere with their interaction networks. 172 , 173 Neuroblastoma RAS viral oncogene homolog (NRAS), historically elusive owing to its intrinsic GTPase activity and lack of tractable binding sites, has been revisited through covalent chemistry and synthetic lethality-based combinations. 174 , 175 In the immuno-oncology domain, forkhead box P3 (FOXP3), a lineage-defining transcription factor in regulatory T cells, is now under exploration for cancer immunotherapy modulation via RNA-targeting approaches and protein interaction disruptors. 176 Collectively, these advances exemplify how the evolving technological landscape is rapidly expanding the druggable frontier. As our mechanistic understanding deepens and modality platforms mature, many of today’s “undruggable” targets may soon follow the path from theoretical challenges to clinical opportunity. However, each breakthrough brings new complexities—be it resistance, toxicity, or delivery—which demand continued innovation to convert initial success into durable clinical impact.

New technologies advancements

In addition to the identification of novel targets, the evolution of therapeutic technologies has profoundly reshaped the landscape of FIC drug development (Fig. 6 ). Emerging modalities—such as cell and gene therapy, ADC, PROTACs and cancer vaccines—not only broaden the spectrum of addressable targets—including those previously considered “undruggable”—but also overcome pharmacologic limitations associated with traditional small molecules or monoclonal antibodies. In parallel, modalities—such as bispecific antibodies and T-cell engagers—enable simultaneous modulation of multiple oncogenic or immunologic pathways, unlocking synergistic effects that are unattainable with monotherapies. This integration of modality-specific capabilities with a deeper mechanistic understanding not only expands therapeutic options but also redefines the scope of what is clinically actionable. The following sections explore how key technological platforms drive this transformation. Fig. 6 Technology platform of approved FIC medicines. ADC: Antibody–drug conjugate, mAb: Monoclonal antibody, BsAb: Bispecific antibody, OVs: Oncolytic viruses

New technologies revive old targets

The resurgence of previously approved drug targets and the sustained momentum in oncology innovation are closely linked to advances in cutting-edge platforms. Rather than introducing new targets, these advances rely on changing the modality—unlocking differentiated pharmacodynamics, tissue penetration, and immune engagement for previously validated mechanisms. For example, CD19 has been successfully targeted across three distinct therapeutic modalities: the first CAR-T cell therapy, tisagenlecleucel, which reprograms patient-derived T cells to eliminate CD19-expressing malignant B cells 15 ; the first ADC therapy, tyrantuximab, which delivers a cytotoxic payload selectively to malignant B cells via CD19 binding 177 ; and the bispecific T-cell engager blinatumomab, which links CD3 on T cells with CD19 on B cells to promote direct immune synapse–mediated cytotoxicity. 38 Owing to these successes, additional CD19-targeting formats—such as chimeric antigen receptor-natural killer (CAR-NK) cells, radioimmunoconjugates, and trispecific antibodies—are currently under clinical investigation. 178 By altering how targets are engaged, these modalities introduce therapeutic advantages that reshape efficacy, resistance patterns, and treatment applicability for well-established oncologic targets.

Cell and gene therapy

Cell and gene therapy (CGT) represents a transformative therapeutic approach that leverages genetic modification or cellular engineering to achieve precise and potentially durable disease control. In oncology, CGT enables highly personalized interventions that go beyond conventional pharmacologic modulation. Our analysis identified five FIC drugs classified as CGT products, including two CAR-T-cell therapies targeting either BCMA or CD19, a gene therapy utilizing interferon alpha-2 (IFNα2), a dendritic cell vaccine incorporating granulocyte macrophage colony-stimulating factor (GM-CSF) and prostatic acid phosphatase (PAP) and a T-cell therapy targeting Epstein–Barr virus (EBV).

The clinical success of CAR-T-cell therapies such as Kymriah (tisagenlecleucel), which targets CD19, and Abecma (idecabtagene vicleucel), which target BCMA in B-cell malignancies, underscores the potential of CGT to induce long-term remission and, in select patients, durable cures. 179 Unlike conventional drugs, these therapies reprogram immune cells to seek, engage, and eliminate cancer cells while retaining immunologic memory and adaptive responsiveness. 180 These advances have sparked intense research interest in CGT, particularly in engineering next-generation immune cells with enhanced specificity and persistence enabled by gene-editing tools such as clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR-Cas9). Examples include PD-1–knockout T cells, which are designed to resist immune suppression, and TCR-modified T cells, which target intracellular tumor antigens via MHC presentation. 181 – 183 As our understanding of antigen escape mechanisms deepens, it will be increasingly informing CAR design optimization, TME adaptation, 184 and rational combination therapies—aiming to increase the durability of remission and extend the therapeutic scope of CGTs. 185

Next-generation CGT platforms aim at improving efficacy, durability, and accessibility. One such direction is the development of allogeneic, or “off-the-shelf”, cell therapies, which use donor-derived immune cells to overcome manufacturing delays and logistical challenges associated with autologous products. Early-stage clinical studies of allogeneic CAR-T cell therapies, such as CTX110, have demonstrated promising efficacy while reducing production timelines from weeks to days. 186 Additional innovations include the use of dual-target CAR-T cells designed to prevent antigen escape and the use of CARs that secrete proinflammatory cytokines such as interleukin-12 (IL-12) to improve infiltration into the tumor microenvironment. 187

In addition to CAR-T cells, additional CGT modalities are expanding the therapeutic landscape. TIL therapy, which leverages polyclonal T cells harvested from the tumor microenvironment, offers a compelling strategy to address antigen heterogeneity and escape. 188 The recent approval of lifileucel has renewed interest in TIL-based products. 189 Therapeutic cancer vaccines aim to stimulate de novo immune responses against tumor-specific antigens, including personalized neoantigens identified through next-generation sequencing and optimized via AI-guided design platforms. These vaccines—delivered via dendritic cells, peptides, or nucleic acid vectors—are under investigation across early- and late-stage cancers. Furthermore, gene therapies delivering cytokines, oncolytic viruses, 190 or synthetic transgenes continue to evolve as complementary approaches to reshape immune responses and augment antitumor efficacy. Together, these modalities highlight the growing diversity of CGT strategies and their potential to offer clinically meaningful options across a wide spectrum of tumor types.

Antibody‒drug conjugate technology

Antibody-drug conjugate therapies (ADCs) have emerged as a powerful class of targeted therapies that combine the antigen specificity of monoclonal antibodies (mAbs) with the cell-killing potency of cytotoxic drugs. Compared with conventional chemotherapy, this modality is designed to deliver cytotoxic agents directly to cancer cells by exploiting tumor-associated surface antigens, thereby maximizing therapeutic efficacy while minimizing systemic toxicity. Through this design, ADCs bridge the pharmacologic precision of biologics with the cell-killing efficiency of chemotherapeutics, offering a highly modular and tunable platform for cancer treatment. 116

Mechanistically, ADCs are composed of three essential components: (1) an antibody that selectively binds to a tumor-specific or overexpressed surface antigen, enabling the selective recognition of malignant cells; (2) a chemical linker that maintains stable circulation in the bloodstream while allowing controlled drug release upon internalization; and (3) a potent cytotoxic payload—typically a microtubule-disrupting agent or a DNA-damaging agent—that exerts lethal effects following intracellular release. Upon antigen binding, ADCs undergo receptor-mediated endocytosis and are trafficked into the lysosomal compartment, where the linker is degraded and the payload is released to exert its cytotoxic effect. Within the FIC landscape, 11 ADCs have been approved as first-in-class therapies, each introducing a novel antigen–payload combination directed against distinct targets—including HER2, trophoblast cell surface antigen 2 (TROP2), EGFR, Nectin-4, BCMA, CD19, CD30 and CD22—spanning solid tumors and hematologic malignancies.

Despite their clinical promise, achieving a favorable therapeutic index remains a central challenge in ADC development. Early-generation ADCs are limited by premature drug release, heterogeneous conjugation profiles, and off-target toxicity, primarily due to unstable linker chemistry and nonspecific payload distribution. 191 , 192 Recent technological advances have addressed these limitations. The development of cleavable linkers responsive to tumor-specific conditions (e.g., low pH and protease activity) has enabled more precise intracellular drug release, whereas site-specific conjugation techniques—such as engineered cysteine residues or enzymatic methods—have improved the drug‒to‒antibody ratio (DAR) uniformity, pharmacokinetics, and product consistency. 193 These innovations have collectively increased the stability, clinical tolerability, and therapeutic index of next-generation ADCs, paving the way for broader application and rational combination strategies in oncology. As of December 2024, 16 ADCs have received global regulatory approval, with newer-generation agents demonstrating improved safety profiles and stronger antitumor activity.

Nevertheless, the long-term safety and efficacy of ADCs remain constrained by several challenges. Resistance mechanisms, such as antigen downregulation, altered drug efflux, and impaired ADC internalization, continue to compromise sustained therapeutic benefit. 194 On-target off-tumor toxicity due to low-level antigen expression in healthy tissues poses a key safety concern. 195 Emerging strategies are focused on next-generation payloads with novel mechanisms of action, such as topoisomerase inhibitors and immune stimulants, along with linker chemistries that provide increased plasma stability and tumor-selective release. Bispecific ADCs requiring dual-antigen recognition are also being explored to improve tumor selectivity and minimize toxicity. Additional innovations include conditionally activated ADCs that respond to tumor-specific enzymatic activity or acidic microenvironments, as well as biomarker-guided patient selection to improve treatment precision. Moreover, combination approaches—such as pairing ADCs with immune checkpoint inhibitors or tumor microenvironment–modulating agents—are under investigation to amplify therapeutic responses and overcome resistance. 196 Collectively, these advances aim to reshape ADCs into more selective, potent, and versatile tools within the expanding arsenal of precision oncology.

Proteolysis-targeting chimera technology

Proteolysis-targeting chimera (PROTAC) technology represents a paradigm shift in targeted protein degradation (TPD), offering a mechanism distinct from traditional occupancy-based inhibition. Instead of transiently blocking protein activity, PROTACs catalyze the degradation of disease-associated proteins by hijacking the ubiquitin–proteasome system (UPS). This event-driven pharmacology offers several advantages, including sustained target suppression, mitigation of resistance owing to protein reactivation, and the ability to engage previously undruggable targets such as transcription factors and scaffolding proteins. Mechanistically, PROTACs consist of three components: (1) a ligand that binds to the target protein, (2) a linker that spatially orients the two functional domains, and (3) an E3 ubiquitin ligase-recruiting ligand. Once internalized, PROTACs simultaneously bind the target protein and an E3 ligase, forming a ternary complex that facilitates ubiquitination and subsequent proteasomal degradation. 197 Crucially, PROTACs act substoichiometrically—a single molecule can trigger the degradation of multiple protein copies—enabling durable effects at lower doses and potentially reducing off-target toxicity. 198

Recent technological advances have accelerated the clinical development of PROTACs that target well-validated oncogenic drivers, such as hormone receptors (e.g., androgen receptor, estrogen receptor) and kinases (e.g., BTK, CDK, BCR-ABL, and KRAS). Many of these proteins are prone to resistance mutations that reduce inhibitor binding or trigger pathway reactivation. Unlike conventional small-molecule inhibitors, which rely on sustained occupancy to suppress activity, PROTACs achieve full degradation of the target protein via the ubiquitin–proteasome system, thereby overcoming mutation-based resistance and enabling deeper pathway suppression. 199 In addition to kinase signaling, PROTACs are being explored against previously inaccessible targets such as MYC and signal transducer and activator of transcription 3 (STAT3), which are oncogenic transcription factors critical in cancer progression but lack classical binding pockets. 200 , 201 Innovations such as dual-targeting PROTACs—designed to degrade two oncogenic proteins simultaneously—are under exploration to address pathway redundancy and further reduce resistance.

However, significant challenges persist. The relatively large size and structural complexity of PROTACs hinder their membrane permeability and oral bioavailability. Medicinal chemistry efforts, particularly in linker optimization and scaffold engineering, are improving pharmacokinetics and tissue penetration. Another bottleneck lies in E3 ligase selection. The majority of current candidates rely on CRBN and VHL, yet expanding the E3 repertoire—including tissue- or disease-specific ligases—may increase precision and reduce systemic toxicity.

Despite their promising potential, several challenges remain in optimizing PROTACs for clinical use. Cell membrane permeability and oral bioavailability remain significant hurdles because of the large molecular weight and complex structures of PROTACs. Medicinal chemistry efforts, particularly in linker optimization and scaffold engineering, are improving pharmacokinetics and tissue penetration. Another bottleneck lies in E3 ligase selection. The majority of current candidates rely on CRBN and VHL E3 ligases; however, expanding the E3 repertoire, such as the inclusion of tissue-specific E3 ligases, may increase precision and reduce systemic toxicity. 202 Emerging strategies also include conditionally activated PROTACs that exploit tumor-specific enzymatic or microenvironmental cues (e.g., pH and hypoxia) to selectively initiate degradation. 203 Biomarker-informed patient selection is being incorporated to improve clinical translation. In addition to monotherapy, PROTACs are combined with immune checkpoint inhibitors, PARP inhibitors, and targeted agents to amplify antitumor responses and delay resistance onset. 204

Cancer vaccine technology advancements

Cancer vaccines have progressed markedly in recent years, driven by advances in immunology, genomics, and delivery platforms. Cancer vaccines are designed to stimulate tumor-specific immune responses capable of recognizing and eliminating tumor cells. They can be classified into prophylactic vaccines, such as human papillomavirus (HPV) and hepatitis B virus (HBV) vaccines, which prevent virus-associated cancers, and therapeutic vaccines, which aim to generate or amplify antitumor immunity in patients with existing cancers. 205

Recent advancements in antigen selection and delivery mechanisms have enhanced immunogenicity, enabled more precise targeting of tumor-specific epitopes, and expanded the clinical utility of cancer vaccines across a growing range of malignancies. A major breakthrough lies in the development of personalized neoantigen vaccines, which exploit tumor-specific mutations unique to each patient. By focusing on these individual, nonself epitopes, neoantigen vaccines circumvent the central tolerance limitations associated with conventional tumor-associated antigens (TAAs), thereby increasing tumor specificity and immunogenicity. 206 The integration of next-generation sequencing (NGS) and artificial intelligence (AI)-driven epitope prediction algorithms has further accelerated the identification of immunogenic neoantigens, streamlining the development of individualized vaccines. 207 By inducing durable T-cell responses and long-lasting immunological memory, neoantigen vaccines are particularly well suited for the adjuvant setting, 208 where eliminating minimal residual disease and preventing recurrence are primary therapeutic goals. This rationale underpins ongoing clinical trials of two mRNA-based personalized vaccines—mRNA-4157 and BNT122—which have demonstrated robust T-cell activation and encouraging relapse-free survival benefits in resected melanoma and lung cancer patients. Both candidates are currently being evaluated in phase II and III trials.

Parallel to antigen discovery, recent innovations in vaccine delivery platforms have expanded the clinical potential of cancer immunization strategies. Among these, mRNA delivery systems have rapidly gained prominence, particularly following the success of mRNA vaccines against COVID-19. 209 Breakthroughs in mRNA stability, codon optimization, and the use of lipid nanoparticle (LNP) carriers have transformed mRNA vaccines from a conceptual platform into a clinically viable modality, enabling efficient in vivo antigen expression, potent immune activation, and rapid, scalable manufacturing. 210 , 211 Beyond mRNA-based vaccines, alternative delivery platforms are advancing. Dendritic cell (DC) vaccines, which rely on the ex vivo loading of patient-derived antigen-presenting cells, offer the advantage of precisely controlling antigen presentation and immune priming. Sipuleucel-T is the only FDA-approved dendritic cell (DC) vaccine approved for the treatment of metastatic prostate cancer, although its clinical efficacy has been modest. Nevertheless, recent progress in ex vivo DC maturation protocols, antigen-loading strategies, and combination approaches—particularly with immune checkpoint inhibitors—has sustained scientific interest in DC vaccines as promising avenues for cancer immunotherapy. Oncolytic virus-based cancer vaccines offer the dual benefits of direct tumor lysis and in situ antigen release, as exemplified by talimogene laherparepvec (T-VEC), an FDA-approved genetically modified herpes simplex virus for melanoma. 212 These platforms also serve as endogenous adjuvants, enhancing antigen spreading and promoting robust systemic immune responses. DNA-based accines, once limited by poor immunogenicity and delivery inefficiency, have been reinvigorated by innovations such as self-amplifying DNA vectors and electroporation-assisted delivery. 213 Among the candidates, INO-5401 has demonstrated encouraging immune activation in early-phase trials for glioblastoma and bladder cancer. 214

Despite notable progress, several critical barriers continue to limit the full therapeutic potential of cancer vaccines. Tumor immune evasion mechanisms—such as antigen loss, immunosuppressive microenvironments, and defective antigen presentation—can dampen vaccine efficacy, particularly in poorly immunogenic (“cold”) tumors. Moreover, the durability of immune responses remains inconsistent, with limited formation of long-term memory T cells in some patients. Interpatient heterogeneity in HLA types, tumor mutational burden, and immune fitness further complicates the generalizability of vaccine responses. In this context, improving delivery systems to increase antigen uptake and T-cell priming while tailoring vaccine design to individual tumor-immune profiles remains essential. In the future, the integration of novel strategies—such as gene-editing tools for antigen engineering, AI-assisted neoantigen selection, and rational combinations with immune-modulating agents—will be pivotal to unlocking the full promise of cancer vaccines as a cornerstone of precision immunotherapy.

New modalities driving multitarget synergies

Target synergy has become a central strategy in first-in-class drug development, as single-target approaches often fall short in addressing pathway redundancy, resistance evolution, and immune escape. Recent advances in drug discovery technologies and molecular engineering—particularly bispecific antibodies and rationally designed multitarget small molecules—have enabled new therapeutic architectures to achieve functional convergence across distinct biological axes. These advances support multitarget synergy through two principal paradigms: intercellular mechanisms, exemplified by bispecific antibodies that bridge immune effector cells and tumor cells to induce targeted cytotoxicity, and intracellular mechanisms, achieved by small molecules that simultaneously inhibit parallel, compensatory, or synthetic lethal pathways within tumor cells. By engaging multiple nodes within or across cellular systems, these strategies increase therapeutic efficacy, reduce acquired resistance, and broaden applicability across complex disease landscapes.

Bispecific antibodies (bsAbs) are capable of engaging two distinct molecular targets simultaneously, offering enhanced therapeutic precision beyond that of single-target therapies. Through mechanisms such as immune cell redirection, blockade of redundant oncogenic pathways, and modulation of immune checkpoints, bsAbs can overcome resistance, amplify immune responses, and address pathway redundancy. T-cell redirection is a key strategy wherein one arm of the bispecific antibody binds CD3 on T cells and the other targets a TAA, thereby recruiting T cells into close proximity with cancer cells. To date, six CD3-based T-cell redirecting bispecific antibodies have been approved as first-in-class drugs. This approach has shown high efficacy in treating hematologic malignancies. These include blinatumomab, which targets CD3 and CD19 for B-cell leukemia, mosunetuzumab, which targets CD3 and CD20 for non-Hodgkin lymphoma, and agents that target BCMA or G protein-coupled receptor, class C, group 5, and member D (GPRC5D) for multiple myeloma. 215 This approach is also actively being translated into other indications, such as the evaluation of anti-CD3/epithelial cell adhesion molecule (EpCAM) as a potential PFIC for epithelial cancers. 216 Another critical mechanism employed by bsAbs is dual receptor inhibition, which involves the simultaneous blockade of two key signaling molecules to suppress compensatory mechanisms and delay resistance. For example, anti-HER3/HER2 bsAbs can concurrently affect HER2-driven oncogenic signaling and HER3-mediated escape pathways. 217 Anti-c-Met/EGFR bispecific agents have shown potential in overcoming resistance to EGFR inhibitors in lung cancers by targeting both primary and bypass signaling routes. 218 A third mechanism centers on dual immune checkpoint blockade. This dual checkpoint blockade, exemplified by anti-CTLA-4/PD-1 bispecifics and anti-lymphocyte activation gene 3 protein (LAG3)/PD-1 bispecifics, enhances T-cell activation and immune system persistence, leading to more durable responses than monotherapies. 219 In addition to these clinically validated strategies, a growing array of next-generation bsAbs is under development—such as NK cell engagers, conditionally activated bsAbs, and tumor-restricted dual TAA binders—offering further avenues for increased specificity, safety, and efficacy across diverse disease contexts.

Multitarget inhibitors constitute another class of FIC drugs, particularly in addressing the limitations of single-target therapies, such as pathway redundancy, adaptive resistance, and tumor heterogeneity. Among the 32 approved FIC drugs in this category, many simultaneously engage multiple oncogenic pathways, epigenetic regulators, immune effectors, and even viral components, thereby increasing therapeutic efficacy and durability. These agents operate through several synergistic strategies. Some inhibitors block redundant or parallel signaling networks, such as dual PI3K isoforms, the FGFR family, or VEGFR blockade, to minimize escape mechanisms. Others directly target resistance-associated pathways, exemplified by EGFR/c-Met or MEK inhibitors that counteract compensatory signaling, which have shown benefits in adaptive resistance contexts. A subset of inhibitors modulates immune signaling axes, such as Janus kinase (JAK)/Tec protein tyrosine kinase (TEC) inhibitors, which recruit both oncogenic and immune pathways in hematologic malignancies. Synthetic lethality-based strategies further expand the multitarget paradigm: while PARP inhibitors primarily target PARP1/2, they exploit coexisting defects in DNA repair (e.g., BRCA mutations) and demonstrate synergy when combined with DNA-damaging agents. 220 In addition, some agents reshape the tumor microenvironment, for example, by inhibiting Src to reduce invasiveness or JAK to relieve immunosuppression. 221 Emerging PFIC multitarget inhibitors are pushing the boundaries even further, with novel compounds under investigation that combine kinase inhibition with epigenetic modulation, target oncogenic signaling alongside immune checkpoint pathways, or integrate antiviral and antioncogenic effects in virus-associated cancers. These pipeline agents reflect a growing emphasis on rational polypharmacology and combinatorial target design to address complex disease biology.

Challenges and perspectives

Challenges

Despite remarkable progress in FIC oncology drug development—ranging from unprecedented target engagement strategies to breakthroughs transformative modality innovations—several enduring challenges continue to impede sustained progress. These challenges unfold across the entire development continuum: from the initial discovery and validation of novel targets, through the translational gap between preclinical success and clinical efficacy, to the global implementation of emerging therapies. Having circumvented specific hurdles, many foundational problems—such as limited chemical tractability, poor disease model predictivity, and biological resistance—continue to re-emerge in new guises. The following sections outline key bottlenecks persisting across the FIC development continuum.

Target discovery bottlenecks

Approximately 10–15% of human proteins are believed to be disease-modifying, and a similar proportion falls within the known druggable proteome. 222 , 223 However, only 1–2% of proteins are thought to meet both criteria, 224 leaving a narrow window for FIC discovery. This narrow intersection greatly restricts the viable target space for novel drug discovery, illustrating that many of the most compelling biological targets remain beyond the reach of current pharmacologic modalities. Compounding this challenge are the methodological constraints of conventional discovery approaches, which span genomic associations, functional perturbations, phenotypic screening, and rational drug design. 225 Genome–wide association studies (GWASs), for example, can link genetic variants to disease phenotypes, but they rarely provide mechanistic insight 226 The associations they yield are often noncausal, requiring downstream validation. Functional perturbation approaches such as RNAi and CRISPR-Cas9 have improved our ability to probe gene function in high-throughput settings, yet these tools introduce inherent biases. They tend to highlight “fitness-essential” genes that are intolerant to knockout but not necessarily tractable due to toxicity or lack of specificity, whereas modulatory genes that may not be essential but are druggable with acceptable safety profiles are often overlooked. This reflects a broader limitation of functional screening: it distorts how targets are identified, prioritized, and validated and contributes to a high false discovery rate in early target nominations.

Phenotypic screening offers a complementary, target-agnostic entry point by identifying compounds that elicit desirable cellular or organismal responses. However, this strategy typically does not reveal the molecular target upfront, making target deconvolution a major bottleneck that often requires chemoproteomic follow-up. Rational design strategies—such as high-throughput screening (HTS), structure-based drug design (SBDD), and ligand- or fragment-based approaches (LBDD/FBDD)—have been widely applied but remain contingent on the availability of well-defined structural information. These methods are largely ineffective against so-called “undruggable” targets, such as protein–protein interactions or intrinsically disordered proteins.

Even when a compelling target is identified, translation into clinically viable therapies remains fraught with uncertainty. Most pathological processes, particularly in oncology, are governed by interconnected and compensatory signaling networks rather than linear pathways. Inhibition of a seemingly essential target often leads to adaptive rewiring through bypass tracks or feedback loops, which not only reduces therapeutic efficacy but also undermines early discovery by generating false positives. Preclinical validation adds another layer of difficulty: murine models and patient-derived xenografts frequently fail to capture the complexity and heterogeneity of human disease, limiting translational fidelity. 227 Targets that appear promising in vitro or in animals often fail in clinical trials because of differences in pathway dynamics, immune interactions, or disease context.

These challenges have become more pronounced with the explosion of multiomics data and AI-enabled prediction tools. While such technologies accelerate hypothesis generation, they also introduce systemic noise, overfitting, and biases due to uneven data representation, inconsistent annotations, or limited diversity. As a result, algorithmically identified targets may lack biological actionability and show limited translational value. Recognizing these limitations, the U.S. FDA has announced plans to phase out mandatory animal testing for certain drug classes, including monoclonal antibodies, in favor of more human-relevant models such as organoids, microphysiological systems, and AI-enhanced simulations. 228

Together, these observations highlight that the barriers to FIC target discovery are rooted not only in the biology of disease but also in the epistemology of how we search for and validate targets. Overcoming these bottlenecks will require more context-aware functional assays, integrative multiscale modeling, and validation platforms that better mirror human pathophysiology—emphasizing not only more data but also better-designed discovery systems.

Clinical translation challenges

Despite unprecedented advances in biomedical science, oncology clinical development continues to suffer from unacceptably high failure rates. Over 90% of investigational drugs entering clinical trials ultimately fail to reach the market, with the majority of failures stemming from insufficient efficacy or unforeseen safety issues. 229 These setbacks often originate not from a single weak link but from a cascade of translational bottlenecks embedded in the current development ecosystem.

A frequent issue lies in the disconnect between robust molecular target engagement and clinical benefit. While compounds may demonstrate clear on-target activity in vitro or in preclinical models, they often fail to elicit durable tumor regression in humans. This shortfall is frequently driven by compensatory signaling, adaptive resistance, and network plasticity—hallmarks of complex oncogenic systems that allow tumors to bypass pharmacological inhibition, even when the molecular mechanism appears valid. 230

Another challenge is the low translational fidelity of widely used preclinical models. Conventional systems such as 2D cultures, murine models, and even patient-derived xenografts (PDXs) often fail to replicate critical features of human disease, including immune microenvironment dynamics, spatial heterogeneity, metabolic context, and evolutionary adaptation. As a result, promising candidates in preclinical pipelines frequently underperform in human trials, particularly when their mechanisms rely on context-dependent cues or cell–cell interactions. 231

In complex diseases such as cancer, high interpatient variability and context-specific biology further complicate trial design and outcome interpretation. The same therapeutic mechanism may elicit divergent responses depending on prior treatments, tumor microenvironmental factors, or genetic background, making reproducibility across patient populations inherently difficult. This heterogeneity is often exacerbated by the reliance on surrogate endpoints such as progression-free survival (PFS) or ORR, which do not consistently predict long-term outcomes such as overall survival or quality of life. 232 , 233 This mismatch has led to premature optimism in early-phase trials and contributed to costly failures in Phase III. 234 As a result, many candidates that show early promise fail in later-phase trials owing to overestimated efficacy or unmet clinical relevance.

In oncology, combination regimens have become a widely adopted strategy to overcome therapeutic resistance and tumor heterogeneity. While conceptually appealing, the clinical translation of such approaches has been far less successful than anticipated. Most combinations fail to demonstrate synergistic efficacy in randomized trials, with nearly 98% offering no significant improvement over standard-of-care therapies. 235 , 236 Several factors contribute to this gap: pathway redundancy and tumor plasticity can blunt intended synergies; pharmacologic antagonism and overlapping toxicities constrain dosing; and the absence of validated predictive biomarkers hampers patient stratification, masking potential benefits in broader trial populations. In many cases, combinations are selected empirically rather than grounded in a robust mechanistic rationale, leading to high attrition despite promising preclinical signals. Moreover, even multitargeted regimens frequently encounter adaptive resistance, particularly in immuno-oncology, where tumors can activate alternative immunosuppressive circuits that blunt antitumor responses and diminish therapeutic efficacy.

Taken together, these limitations reveal that the failure to translate early mechanistic promise into clinical success is rooted in multilayered disconnects—between target engagement and durable efficacy, between preclinical models and human pathophysiology and between therapeutic strategies and patient heterogeneity. Overcoming these barriers will require more predictive experimental systems, refined stratification tools, and trial designs aligned with the complex, adaptive nature of human disease.

Access and equity barriers

Despite rapid biomedical innovation, access to first-in-class therapies remains profoundly unequal across regions. Our analysis shows that over 50% of FIC oncology drugs are first approved in the U.S., with subsequent authorizations in Europe and other high-income countries often delayed by months to years. 237 , 238 In China, sweeping regulatory reforms since 2015 have significantly narrowed this gap—from historical delays exceeding five years to nearly parallel approvals with the U.S. for select therapies. 26 , 239 However, in many low- and middle-income countries (LMICs), access remains sporadic or absent. A study of new drug launch times across 75 countries from 1982 to 2024 reported a median delay of 2.7 years in high-income countries versus 8.0 years in low-income countries from the first launch globally. 240 These lags are not inconsequential: in aggressive cancers, even 3–6 months of delayed access can translate into lost curative windows and excess mortality. 241 , 242

A core driver of these disparities is the uneven capacity of national regulatory agencies. National agencies differ in their technical infrastructure, clinical evaluation expertise, and degree of reliance on foreign approvals or reference agencies. The WHO’s Global Benchmarking Tool (GBT) has been instrumental in assessing the maturity levels of regulatory systems. Only 50 countries (26%)—approximately one quarter globally—meet the top two maturity levels. 243 – 245 Even among these, few possess the technical infrastructure and evaluative depth required for assessing complex modalities and first-in-class mechanisms. Many LMIC regulators—such as those in Southeast Asia—rely on WHO prequalification or decisions from WHO listing authorities (WLAs), such as the FDA or EMA. 246 Beyond regulatory capacity, uneven access is also driven by imbalanced submission strategies, where companies prioritize high-income markets with greater commercial returns while delaying or forgoing filings in lower-income regions owing to perceived limited profitability or logistical complexity. 247 , 248

Even post-approval, access remains constrained by multiple implementation gaps. High-cost therapies like CAR-T or gene-editing agents may be technically authorized in principle but remain inaccessible in many settings owing to limitations in infrastructure, care delivery models, and national reimbursement capacity. For example, although CAR-T cell therapies have been approved in more than 30 countries, their real-world use is concentrated in only a handful of nations with the requisite clinical and manufacturing ecosystems. 249 , 250

Collectively, these barriers illustrate that equitable access to FIC therapies depends not only on regulatory acceleration but also on global coordination across market entry strategies, health system preparedness, and sustainable financing. Without systemic alignment, the promise of innovation will remain unrealized for large segments of the global population.

Perspectives

To overcome the persistent limitations of target tractability, development efficiency, and global accessibility, first-in-class innovation is now entering a new phase—shaped by advances in AI-driven discovery, next-generation modalities, and globally coordinated translation strategies. These evolving fronts not only offer solutions to long-standing bottlenecks but also signal a shift toward more programmable, precise, and inclusive models of therapeutic innovation.

Harnessing artificial intelligence for innovation

Despite ongoing concerns about data bias and translational limitations, AI has emerged as a powerful enabler of innovation across the first-in-class drug development continuum, with growing interest in its application to improve multiple stages of the drug discovery pipeline, including de novo molecular design and optimization, structure-based drug design, and preclinical and clinical development. 251 Traditional paradigms for target identification and molecule optimization have long relied on labor-intensive, trial‒and-error methodologies, which are often constrained by biological complexity and high attrition rates. In contrast, the rise of AI—particularly foundation models and multimodal learning systems—has catalyzed a shift toward data-centric, systems-level strategies that enhance both discovery breadth and development efficiency, spanning stages from target identification and structure prediction to molecule generation and preclinical optimization. 252 , 253 Notable platforms include AlphaFold 3, which dramatically improves protein structure prediction 254 ; DeepMind’s Enformer, which is capable of predicting gene expression and regulatory effects from DNA sequences; and Insilico Medicine’s Pharma.AI platform for end-to-end target-to-candidate generation and BenevolentAI’s knowledge graph–driven systems for target identification and clinical prioritization. BioNTech’s BioNEO and Recursion’s automated phenotypic screening pipelines further demonstrate how AI is accelerating compound screening, mode-of-action prediction, and lead optimization across diverse indications. These capabilities are already moving beyond theory. By 2021, AI-driven biotech companies were advancing preclinical pipelines at a pace comparable to that of the top 20 pharmaceutical firms 253 —underscoring AI’s growing role in real-world drug development.

One of the most transformative contributions of AI is target identification. By integrating multiomic (genomics, proteomics, or transcriptomics), structural, and literature-derived knowledge graphs, AI platforms can rapidly uncover potential therapeutic targets with remarkable speed and precision. 255 For example, Finan et al. designed a computational approach to combine data from numerous existing GWASs to identify druggable proteins, connect them with known drugs where available, and facilitate the design of new targeted therapeutics. 256 The integration of multiomics data with graph convolutional networks (GCNs) has demonstrated efficacy in identifying novel cancer-associated genes and elucidating their molecular mechanisms. 257 Companies such as Insilico Medicine have successfully employed AI-driven platforms such as PandaOmics™ to uncover previously unreported therapeutic targets for amyotrophic lateral sclerosis (ALS). 258 BenevolentAI’s knowledge graph, which integrates over 280 million scientific documents, identified serine/arginine-rich splicing factor 6 (SRSF6) spliceosome dysregulation as a key factor in ALS pathogenesis, leading to the development of antisense oligonucleotide therapy currently in phase II trials. 259 In parallel, large language models (LLMs), such as Microsoft’s BioGPT 260 and Insilico Medicine’s ChatPandaGPT, 261 are revolutionizing biomedical text mining by analyzing millions of scientific publications to establish complex relationships among diseases, genes, and biological pathways. The efficiency of these AI-driven approaches is exemplified by the Pharma of Insilico Medicine. AI, which facilitated the identification and optimization of a preclinical candidate drug for metabolic dysfunction-associated steatohepatitis (MASH) within just four months, demonstrated AI’s capacity to extract actionable insights and accelerate the early stages of drug discovery. Advanced platforms that integrate natural language processing, knowledge graphs, and deep learning are now mining biomedical literature, omics datasets, and disease networks to uncover molecular vulnerabilities that are often missed by conventional approaches. For example, Insilico Medicine’s generative AI engine identified lysine acetyltransferase 6 (KAT6), a histone acetyltransferase implicated in oncogenic transcriptional regulation, as a novel epigenetic target, launching over 20 pipeline programs. Evaxion Biotech’s AI-Immunology™ integrated platform reportedly identified new immuno-oncology targets within hours, and Gen1E Lifesciences used its integrated AI-driven discovery system to generate 21 candidates within only 2.5 years. These cases illustrate AI’s potential to compress discovery timelines that traditionally span decades and expand the therapeutic frontier beyond well-established pathways.

The transformative impact of AI on pharmaceutical R&D is increasingly evident through quantifiable milestones. Several recent achievements exemplify how AI is reshaping drug R&D processes. For example, Generate Biomedicines employed structure-prediction algorithms to rationally design glutathione peroxidase 8 (GPX8), a KRAS G12D-targeting PROTAC degrader, achieving crystallographic validation with subangstrom precision. In silico Medicine’s ISM001-055, 262 a small-molecule TRAF2- and NCK-interacting kinase (TNIK) inhibitor for idiopathic pulmonary fibrosis, progressed from target discovery to first-in-human trials within just 30 months, setting a new benchmark for AI-enabled drug discovery. These cases reflect a broader paradigm shift wherein AI increasingly interfaces with wet-lab experimentation, synthetic biology, and high-throughput automation, thereby increasing both the efficiency and precision of the preclinical pipeline.

As AI-powered methodologies continue to evolve, they hold the promise to compress development timelines, expand the therapeutic landscape beyond canonical targets, and ultimately translate foundational insights into clinically meaningful therapies. However, their capacity to predict efficacy in complex human systems remains largely unvalidated, as most AI-generated candidates are still awaiting proof of durable clinical benefit in phase II or III trials. 263 , 264 While regulatory bodies such as the FDA, EMA and NMPA have expressed growing support for AI integration through pilot programs and guidance initiatives, a core challenge persists in how to systematically assess the validity and reliability of AI-generated outputs. 265 – 267 Current frameworks remain insufficiently equipped to evaluate predictions derived from opaque training datasets, probabilistic algorithms, or generative models that produce novel targets and chemical structures lacking precedent in traditional pharmacology. This gap in evaluative infrastructure introduces uncertainty in decision-making and slows the path from in silico insight to real-world application. Moving forward, it is imperative to establish new standards for algorithm transparency, data provenance, model validation, and evidence thresholds tailored to AI-enabled discovery. Only through such structured integration into the regulatory ecosystem can AI fulfill its potential to reshape the drug development landscape while maintaining the rigor of clinical translation.

Unlocking the promise of next-generation modalities

Analyses of PFIC pipelines reveal that next-generation modalities now represent a growing share of innovation—outpacing conventional FIC drugs in their ability to engage biologically validated but clinically elusive targets. As conventional therapeutic modalities approach their biological and technological limits, next-generation platforms offer not only mechanistic novelty but also the potential to overcome long-standing barriers in drug development. The next frontier lies not in the platforms themselves—but in how these modalities evolve to overcome complexity, improve scalability and unlock previously inaccessible biological space.

Cellular therapies are undergoing a profound transformation, moving beyond autologous CAR-T-cell products toward diverse and programmable therapeutic classes. 268 While CAR-T cells have demonstrated remarkable efficacy in treating hematologic malignancies, their broader application has been constrained by challenges such as antigen escape, manufacturing bottlenecks, and immunosuppressive microenvironments. In response, the field has expanded to include a range of engineered cell types—including TCR-T cells, NK cells, tumor-infiltrating lymphocytes (TILs), and induced pluripotent stem cell (iPSC)-derived immune cells—each offering distinct advantages in tackling disease-specific barriers. Innovations are converging along several fronts. Off-the-shelf allogeneic products, enabled by genome editing and immune cloaking strategies, aim to eliminate the need for patient-specific manufacturing while expanding access and scalability. 269 At the same time, in vivo engineering approaches are redefining the production model entirely—using mRNA, viral vectors, or lipid nanoparticles to reprogram endogenous immune cells directly within the patient, offering a more flexible and rapid path to treatment. Complementing these advances, synthetic immune circuits are being incorporated into both autologous and allogeneic therapies to improve safety, specificity, and responsiveness. 270 By programming immune cells to integrate multiple cues—such as antigen density, microenvironmental context, or spatial positioning—researchers are designing next-generation systems capable of dynamic, real-time adaptation. Together, these developments signal a shift toward programmable cellular immunotherapies that are not limited by indication or format but are instead designed to manage the complexity of cancer, autoimmunity, and infectious disease with increasing precision and resilience. As these platforms mature, they have the potential to achieve more consistent efficacy, greater accessibility, and broader clinical relevance across disease spectra previously unreachable by conventional cell therapy.

Furthermore, recognized as a paradigm-shifting approach, targeted protein degradation is now moving beyond PROTACs toward a broader, modular targeted protein degradation (TPD) landscape that redefines how pathogenic proteins are eliminated rather than inhibited. 204 Future advancements are extending degradative pharmacology beyond the ubiquitin–proteasome system to incorporate autophagy- and lysosome-mediated pathways, such as autophagy-targeting chimeras (AUTACs) and lysosome-targeting chimeras (LYTACs). 271 These systems unlock access to extracellular and membrane proteins long considered undruggable, broadening the degradome beyond cytosolic targets. In parallel, conditional degraders responsive to hypoxia, tumor-associated proteases, or pH changes are being developed to increase spatial and temporal precision. Advances in E3 ligase profiling and structure-guided ligand design—often AI-assisted—are enabling rational expansion of ligase–substrate pairs, including tissue-selective or inducible ligases. 272 , 273 Next-generation degradation platforms are also integrated with programmable delivery vehicles, such as ADCs, nanoparticles, or exosomes, to improve bioavailability and tissue penetration. Rather than acting as static inhibitors, these intelligent systems operate as catalytic, context-aware agents that can be tuned for degradation strength, specificity, and duration. 274 Together, these innovations point toward a future in which targeted degradation is not a modality but an adaptable framework—capable of reshaping the druggable proteome and expanding FIC opportunities in previously unreachable therapeutic spaces.

These innovations are not merely technical upgrades but also reflect a growing ability to design therapies that adapt to biological complexity, operate across scales and unlock previously inaccessible therapeutic space. As engineering precision, delivery systems, and biomarker integration continue to advance, such platforms are poised to shape a more modular, durable, and mechanism-driven future of FIC innovation.

Enabling global translation of first-in-class innovation

As FIC innovations increasingly rely on AI-guided target discovery and next-generation modalities such as cell therapy and targeted protein degradation, their global translation is no longer a downstream consideration but a strategic imperative. Emerging international frameworks are fostering more synchronized development and approval of novel therapies across regions. Initiatives such as the WHO’s Global Benchmarking Tool (GBT), Project Orbis led by the U.S. FDA, and regional joint assessments such as ZAZIBONA from Africa and Joint Assessment from ASEAN countries have helped accelerate access by promoting reliance on regulatory evaluations from more mature authorities. 245 , 275 These mechanisms not only reduce duplication and approval lag but also lay the groundwork for mutual learning and regulatory convergence.

Scientific convergence is also accelerating. Nations with complementary strengths are engaging in cross-border clinical research, technology transfer, and regulatory learning. For instance, China’s dual-track regulatory model for cell therapies, which allows both IND and investigator-initiated trial pathways, has enabled rapid domestic translation and made China a global hub for CGT development, 28 accounting for 51.7% of the global pipeline. As global R&D ecosystems become more interconnected, joint clinical protocols, multiregional trials, and harmonized data standards are enabling earlier validation of FIC assets across diverse populations. AI-powered predictions, omics-driven target selection, and real-world evidence from decentralized health systems are being integrated across borders, creating a collaborative feedback loop from discovery to deployment.

To support broader uptake and implementation, emerging global mechanisms now encompass not only regulatory and scientific coordination but also access-enabling strategies. Tiered pricing models, joint procurement programs, and technology transfer partnerships are helping ensure that FIC therapies reach patients beyond high-income countries. Strategic licensing, acquisitions, and co-commercialization partnerships remain essential tools for expanding reach and building sustainable delivery models. Despite ongoing geopolitical tensions, the momentum toward global interdependence in pharmaceutical innovation continues to grow. 29

Ultimately, enabling the global translation of FIC innovation requires more than efficient regulatory pathways—it depends on strategic alignment across policy, science, and market access. By embedding collaboration into every stage from target discovery to product delivery, the industry can ensure that transformative therapies benefit patients worldwide, not only where they are invented.

Conclusion

The global increase in marketed FIC drugs and candidates has been propelled by the discovery of new targets or the application of cutting-edge technologies. By systematically analyzing global trends from 2009 to 2024, including both approved therapies and clinical-stage PFIC candidates, this Review reveals a rapidly diversifying innovation landscape driven by advances in molecular target discovery, enabling technologies and evolving R&D strategies. On the basis of our novelty-type classification, while approved FIC drugs primarily emphasize novel targets, PFIC candidates increasingly leverage advanced therapeutic platforms. Despite these achievements, enduring challenges such as incomplete target validation, development inefficiencies, and regulatory inertia continue to limit the full realization of FIC therapeutic potential. Transformative platforms such as cell therapies, gene therapies, ADCs, PROTACs, cancer vaccines, and bispecific antibodies have broadened the druggable space and enabled the targeting of previously intractable mechanisms. Three strategic levers will be pivotal in unlocking the next wave of transformative cancer treatments: deeper integration of AI to increase early target discovery; expanded adoption of next-generation modalities capable of modulating traditionally undruggable targets; and stronger international regulation and coordination to accelerate access to and reduce global disparities in cancer care. Harnessing these opportunities will require not only scientific ingenuity but also policy innovation and global collaboration—factors that will decisively shape the future of oncology drug innovation.

Supplementary information

Supplementary materials

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

Supplementary information

The online version contains supplementary material available at 10.1038/s41392-026-02606-7.

Acknowledgements

This work was funded by the National Natural Science Foundation of China (72374119), the State Key Laboratory of Drug Regulatory Science (2024SKLDRS0225), the Beijing Nova Program and China Society for Drug Regulation (2025-Y-Y-005). The authors gratefully acknowledge Dazhi Pang (Tsinghua University) for helping to modify the figures, and Caleb Alexander (Johns Hopkins University) and Xuemin Zhu (University of Oxford) for helpful feedback on earlier manuscript drafts and sincerely thank Xue Wang, Wei Wei, Jiaxuan Yang, Xiaoyin Bai, and Shuya Zhang for their valuable insights and constructive suggestions during the early development of this manuscript.

Author contributions

G.L. and Q.Z. were involved in the conception and design of the review. X.M., G.L. and Z.W. wrote the paper and prepared the figures and tables. S.K., Y.Y., N.A.D. and M.T.L. critically reviewed and edited the manuscript. All the authors have read and approved the article.

Competing interests

M.T.L. is a member of the Scientific Advisory Boards of KSQ, Inc., BioCytics, Zai Laboratories, Appel Sauce Studios, Zola Therapeutics, and the Ludwig Institute. Q.Z. is the editorial board member of Signal Transduction and Targeted Therapy, but he has not been involved in the process of the manuscript handling. Other authors declare no competing interests.

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