The advent of precision oncology has brought substantial advancements in cancer therapy, yet it has been accompanied by equally complex resistance mechanisms. Among these mechanisms, histological transformations can compromise the effectiveness of targeted therapies, resulting in a loss of clinical benefit following initial success. Understanding these evolutionary processes is crucial for developing the next generation of cancer treatments that can effectively combat resistance. This review examines histological transformation as a key mechanism of resistance to anticancer therapies, driven by various forms of tumor plasticity, and explores into the underlying processes and mechanisms that drive these changes. We also discuss how precision oncology and an appreciation of cancer plasticity can be leveraged to overcome histological transformation and lead to improved patient outcomes.

In this issue of Cancer Cell, Shi et al. report encouraging early-phase results combining HRS-4642, an allele-specific KRAS G12D inhibitor, with the PD-L1 inhibitor adebrelimab in previously treated metastatic pancreatic cancer. The intravenous combination was safe and well tolerated, notably sparing patients the gastrointestinal toxicity common to oral KRAS inhibitors, and achieved a promising 43% response rate at the recommended dose.

The availability of approved antibody-drug conjugates (ADCs) has rapidly expanded across oncology indications, yet biomarker development remains dominated by semi-quantitative immunohistochemistry. Robust biomarkers are needed to improve patient selection, guide therapeutic sequencing and identify resistance mechanisms that inform rational combinations. ADC activity depends on target antigen expression, linker chemistry and payload characteristics all within the context of the tumour microenvironment. Consequently, treatment response cannot be predicted solely by target expression. A more comprehensive biomarker framework is required that accounts for antigen abundance and accessibility, intracellular trafficking and linker cleavage, and tumour susceptibility to the payload. Furthermore, biomarkers of toxicity have been largely overlooked, even though toxicity can be equally determinant of clinical utility. In this Review, we outline a modular framework for ADC biomarker development organized around these components. We distinguish established evidence from emerging strategies and discuss technologies that could enable assessment of these determinants. We consider how modular biomarkers might inform patient selection, therapeutic sequencing, rational combinations, dose optimization and regulatory strategy while highlighting the various challenges that must be addressed before broad clinical adoption. Harmonized development across trials, tumour types and geographical regions will be essential to move biomarker development beyond empirical target-expression thresholds.

Adoptive cellular therapies (ACT) have reshaped the treatment landscape of hematologic malignancies and are increasingly being explored in solid tumors. Key approaches include chimeric antigen receptor T-cell (CAR-T) therapy, which targets tumor-associated surface antigens in an HLA-independent manner, and T-cell receptor-engineered T-cell (TCR-T) therapy, which enables recognition of intracellular tumor antigens presented by major histocompatibility complex molecules. However, the application of CAR-T and TCR-T in solid tumors remains limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, manufacturing complexity, and safety concerns related to on-target/off-tumor effects and cytokine-mediated toxicities. The American Society for Clinical Oncology (ASCO) Annual Meeting is a key platform for the presentation of cutting-edge clinical data, and in this brief correspondence, we summarize the principal early-phase clinical trials with CAR-T and TCR-T for solid tumors reported at the 2026 meeting.

MET exon 14 (METex14) skipping alterations represent actionable oncogenic drivers in non-small cell lung cancer (NSCLC). However, noncanonical intronic splice-site variants are frequently classified as variants of uncertain significance (VUS) on DNA-based next-generation sequencing (NGS), limiting timely therapeutic decision making. We describe two patients with advanced NSCLC harboring novel intronic deletions affecting the MET exon 14 splice acceptor region, initially classified as VUS. Integrated transcript level analysis using RNA sequencing and orthogonal validation by reverse transcription PCR (RT-PCR) was performed to assess functional impact. RNA-based analysis in both cases demonstrated METex14 skipping through identification of exon 13-15 junction reads, which was further confirmed by RT-PCR. Based on functional evidence, both variants were reclassified as clinically actionable alterations (AMP/ASCO/CAP Tier II), directly influencing therapeutic management with MET-targeted tyrosine kinase inhibitors. Early clinical stabilization was observed in both patients. These findings support the routine incorporation of RNA-based validation strategies to improve accurate interpretation of noncanonical MET splice-site variants. We propose a practical diagnostic workflow for evaluation and reclassification of MET splice-site VUS, emphasizing the role of transcript-level evidence in enabling accurate molecular reporting and guiding targeted therapy.

Non-conventional prostate cancer histologies represent a small but clinically significant subset characterised by aggressive behaviour, atypical biomarker profiles, and reduced dependence on androgen receptor signalling. Evidence indicates these histologies reflect dynamic biological states driven by genomic instability, lineage plasticity, and therapeutic selection rather than static morphologic entities, with several morphologies acting as accessible, if imperfect, surrogates for actionable alterations. We performed a translational narrative review integrating anatomic pathology, genomic and epigenomic biology, and biomarker-selected therapy, searching PubMed/MEDLINE, Embase, Cochrane CENTRAL, the ASCO Meeting Library, ESMO publications, and APCCC through May 2026, spanning neuroendocrine, ductal, intraductal, cribriform, adenosquamous, sarcomatoid, adenoid cystic, signet ring cell, and mucinous subtypes. These histologies are individually uncommon but are consistently associated with advanced stage and inferior survival. Neuroendocrine prostate cancer is the most aggressive phenotype and a major mechanism of resistance to AR-directed therapy, driven by combined RB1 and TP53 loss, epigenetic reprogramming, and lineage plasticity, and marked by DLL3 expression. Cribriform and intraductal carcinoma are often enriched for BRCA2 and DNA-repair deficiency, whereas ductal differentiation is associated with mismatch-repair deficiency in a subset, with implications for PARP inhibition and checkpoint blockade. Emerging strategies include platinum-based chemoimmunotherapy and investigational lineage-directed agents targeting DLL3, STEAP1, KLK2, and TROP-2, alongside radioligands. These histologies are best viewed as biologically distinct, evolving disease states. By integrating pathology, molecular biology, and biomarker-selected therapy into one translational pathway, this review reframes non-conventional histology as a prompt for early molecular characterisation and adaptive, biology-driven treatment.

Trophoblast cell-surface antigen-2 (Trop-2) is overexpressed in most breast cancers, including about 90% of triple-negative breast cancers (TNBC) and more than half of hormone receptor-positive/HER2-negative (HR+/HER2-) tumors, with limited expression in normal tissues, making it an attractive therapeutic target. Sacituzumab govitecan (SG), the first Trop-2-directed antibody-drug conjugate (ADC) delivers the topoisomerase I inhibitor SN-38 to cancer cells and has changed the treatment of metastatic breast cancer (mBC).

Globally, breast cancer is the most frequently diagnosed malignancy in women, with the HER2-low subtype (IHC 1+ or IHC 2+/ISH-) accounting for approximately 45%-55% of all invasive breast cancer cases. Conventional HER2-targeted therapies are ineffective for this subtype, and treatment has long relied on endocrine therapy or chemotherapy, with a median overall survival of less than 18 months after resistance development. This narrative review synthesizes evidence from clinical trials identified through systematic searches of the PubMed, ASCO, and ESMO databases until December 2025. Antibody-drug conjugates (ADCs) combine targeted delivery with potent cytotoxicity. The next-generation ADC trastuzumab deruxtecan (T-DXd) has achieved a breakthrough in the treatment of HER2-low breast cancer, attributed to its high drug-to-antibody ratio (DAR = 8), robust bystander effect, and non-classical killing mechanisms mediated by the tumor microenvironment. The landmark DESTINY-Breast04 trial provided the first definitive evidence that T-DXd significantly prolongs progression-free survival (PFS) and overall survival (OS). The DESTINY-Breast06 study further expanded the population that may benefit to include patients with HER2-ultralow expression and moved treatment to an earlier line, after endocrine therapy failure and before chemotherapy initiation. Chinese ADCs, such as disitamab vedotin (objective response rate [ORR], 33.3%), SHR-A1811, and MRG002, have also shown promising efficacy. However, resistance mechanisms, including target loss, impaired endocytosis, payload efflux, abnormalities in DNA repair, and suppression of the immune microenvironment, are emerging. Combination strategies involving endocrine therapy, immune checkpoint inhibitors, and HER2 tyrosine kinase inhibitors are expected to overcome resistance and enhance the efficacy of treatment. This review provides a comprehensive overview of ADC development in advanced HER2-low breast cancer, summarizes key clinical data, resistance mechanisms, and combination strategies, and discusses future directions, including biomarker development and optimal treatment sequencing, to guide clinical practice and future research in this area.