Search Results (1,251)

Metastatic breast cancer (MBC) remains incurable because of tumor evolution. Despite advances in targeted therapies—CDK4/6 inhibitors, PIK3 inhibitors, HER2-directed agents, and antibody–drug conjugates—median overall survival is modest, with resistance emerging in nearly all patients. From an evolutionary perspective, standard continuous maximum tolerated dose (MTD) therapy may create intense selective pressure that reduces treatment-sensitive cells and, in some incurable and resistance-prone settings, could permit competitive release of resistant clones. While MTD remains the guideline-endorsed standard of care in many metastatic settings and has produced substantial survival gains, the eco-evolutionary framework highlights a potential trade-off rather than a categorical failure of MTD. Cancer is not just a genetic disease but an evolving ecosystem where cell populations compete for limited resources. Resistant cells typically carry a fitness cost—slower growth in the absence of treatment—creating an exploitable vulnerability. By preserving treatment-sensitive cells through dose modulation or treatment holidays (adaptive therapy), we can harness competitive suppression to control resistant populations and prolong disease control, potentially doubling time to progression compared to continuous MTD. This primer translates these ideas into plain language for clinical trial application. We explain four core eco-evolutionary principles every breast oncologist should know, review emerging evidence from adaptive therapy trials in breast and other cancers, and discuss practical implementation strategies to incorporate into future trials. The goal is not cure through eradication, but long-term control through evolutionary management. These evolution-informed strategies may, in selected contexts, help delay resistance and prolong disease control, and represent a complementary framework that warrants prospective testing. Full article

Autoimmune diseases encompass nearly 100 distinct conditions characterized by dysregulated immune responses against self-antigens, resulting in tissue damage, chronic inflammation, and substantial morbidity. Over recent decades, the global burden of autoimmune diseases has increased, while their therapeutic management has undergone a paradigm shift from broad, nonspecific immunosuppression toward targeted biologic therapies. Among these, antibody-based therapeutics, including monoclonal antibodies targeting cytokines, cell-surface molecules, and co-stimulatory pathways, have transformed the treatment of numerous systemic and organ-specific autoimmune disorders. Nevertheless, important challenges remain, including primary non-response, secondary loss of efficacy related to immunogenicity or disease adaptation, increased susceptibility to infections, and mechanistic redundancy among therapeutic targets. This review provides a comprehensive overview of the cellular and molecular mechanisms underlying antibody-based therapies, summarizes major therapeutic target classes across autoimmune diseases, and examines their clinical and mechanistic limitations. Emerging therapeutic platforms, including bispecific antibodies, antibody–drug conjugates (ADCs), novel Fc-engineering, and cellular approaches such as CD19-targeted chimeric antigen receptor (CAR)-T therapy, are also discussed. Finally, antigen-specific immunotherapies designed to restore antigen-specific immune tolerance while preserving systemic host defense are explored. These approaches may represent an important next frontier in the treatment of autoimmune diseases, moving beyond broad systemic immune modulation toward more selective and durable immune control. Full article

CD97 is an adhesion G-protein-coupled receptor encoded by ADGRE5 that integrates extracellular signals (including cell adhesion, ligand binding, and mechanical stimulation) with intracellular signal transduction. Recent structural studies have further elucidated tethered/intramolecular agonist (TIA)/Stachel recognition and engagement of the seven-transmembrane domain (7TMD), activation-associated 7TMD conformational changes, and G-protein coupling, including the structural basis for the preferential coupling of CD97 to G13. Currently, antibody–drug conjugates (ADCs) targeting CD97 are supported by in vitro proof-of-concept evidence, whereas chimeric antigen receptor (CAR) strategies have shown antitumor activity in animal models of glioblastoma (GBM) and acute myeloid leukemia (AML). Existing research indicates that CD97 is involved in maintaining stem-like states, invasion and metastasis, metabolic adaptation, and stress survival in certain tumors, and its function varies depending on tumor type and cellular environment. Because CD97 is also expressed in normal immune cells and various nonhematopoietic tissues, systemic targeted therapy may be limited by on-target/off-tumor toxicity. This article reviews the latest advances in CD97 structure and signal transduction, and explores its tumor-related functions, biomarker value, evidence for ADC and CAR-related therapies, as well as early exploratory directions involving RNA-mediated downregulation and structure-guided interventions. Full article

Background/Objectives: HER2-directed antibody–drug conjugates have expanded the clinical relevance of low-level HER2 expression. However, the prevalence and clinical significance of HER2-ultralow expression in gynecologic malignancies remain insufficiently defined. This study characterized the full spectrum of HER2 expression in endometrial carcinoma (EC) and high-grade serous ovarian carcinoma (HGSOC), including matched metastatic lesions. Methods: HER2 expression was assessed by immunohistochemistry in tissue microarrays from 117 EC and 52 HGSOC patients. Available matched metastatic lesions were analyzed in 23 EC and 18 HGSOC cases. HER2 expression was categorized as zero, ultralow, 1+, 2+, or 3+. Associations with clinicopathological parameters and progression-free survival were evaluated. Results: HER2-ultralow expression was common in primary tumors, occurring in 49/117 EC cases (41.9%) and 11/52 HGSOC cases (21.2%), whereas HER2 3+ expression was rare (EC: 2/117, 1.7%; HGSOC: 1/52, 1.9%). HER2 expression in primary tumors was associated with progression-free survival in both entities, with HER2-zero tumors showing the longest estimated progression-free survival. HER2 score discordance between matched primary tumors and metastases occurred in 16/23 EC cases (69.6%) and 8/18 HGSOC cases (44.4%). Conclusions: HER2-ultralow expression represents a frequent and previously underrecognized category in EC and HGSOC. While its prognostic impact remains limited, the high prevalence of HER2-ultralow tumors suggests potential relevance for future HER2-targeted therapeutic strategies. Prospective studies are needed to determine whether this subgroup may benefit from a HER2-targeted therapy. Full article

Background/Objectives: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy has been the standard of care for muscle-invasive bladder cancer (MIBC) for two decades, yet a substantial proportion of patients derive no benefit. As antibody–drug conjugates and immune checkpoint inhibitors reshape perioperative treatment, it is unclear which patients retain meaningful benefit from platinum. We describe long-term outcomes and exploratory paired immune and genomic analyses in a single-centre cohort treated with dose-dense MVAC (dd-MVAC). Methods: We retrospectively identified 54 consecutive patients with MIBC treated with neoadjuvant dd-MVAC between November 2013 and November 2019. Forty-two underwent radical cystectomy and are assessable for pathologic response. Immunohistochemistry for CD3, CD8, FOXP3, PD-1, PD-L1, PD-L2, and NY-ESO-1 was evaluable in 31 baseline specimens and 22 paired specimens; paired genomic profiling was evaluable in 12 cases, with paired tumour mutational burden (TMB) in 10 by whole-exome sequencing and 7 by TSO-500. Paired analyses necessarily exclude patients achieving a pathologic complete response (pCR), who have no residual tumour, and most early progressors. Results: pCR was achieved in 11/42 operated patients (26%, 95% CI 15–41). Median follow-up was 87 months (IQR 24–104). Hydronephrosis was the only baseline factor associated with absence of pCR (p = 0.016). Within the operated cohort, pCR was associated with longer recurrence-free survival (log-rank p = 0.017), but the difference in overall survival did not reach significance (p = 0.121). NAC reduced intratumoral FOXP3 (q = 0.001), NY-ESO-1 (q = 0.013), PD-L2 (q = 0.013), and CD3 (q = 0.043) after correction for multiple comparisons, whereas TMB showed no significant change (TSO-500 p = 0.67; WES p = 0.86). No statistically significant association was detected between any baseline immune marker, including PD-L1, and pCR. The mutational landscape was largely concordant before and after NAC. Conclusions: This study was exploratory and was not powered to validate predictive biomarkers. In this long-term cohort, dd-MVAC was associated with measurable depletion of intratumoral immune populations in chemoresistant tumours, while paired genomic profiles remained broadly concordant. No pre-treatment biomarker identified platinum-refractory patients, but the small evaluable subsets mean these are hypothesis-generating rather than negative findings, and prospective studies with pre-specified biomarker endpoints are required. Full article

Bispecific antibodies (bsAbs) and bispecific antibody–drug conjugates (bsADCs) represent promising classes of emerging targeted therapeutics with the potential to overcome tumor heterogeneity and resistance in colorectal cancer (CRC). BsAbs can simultaneously engage multiple tumor antigens or immune cells or bind two distinct epitopes within a single target, enabling mechanisms of action beyond the capabilities of monoclonal antibodies. Bispecific T cell engagers facilitate targeted destruction of tumors through immune cell recruitment, while dual immune checkpoint inhibitors enhance immune activation by blocking T cell inhibitory signals. Furthermore, bsAbs can mediate dual signaling pathway inhibition through binding multiple receptor tyrosine kinase receptors or other tumor cell surface proteins. BsADCs integrate the dual-antigen recognition of bsAbs with targeted payload delivery, utilizing receptor-mediated endocytosis to deliver potent cytotoxic payloads selectively to CRC cells, while minimizing systemic toxicity. Recent advances in bsAb engineering, linker chemistry, site-specific conjugation, and payload design have accelerated the development of bsADCs for solid tumors, including CRC. BsAbs and bsADCs provide opportunities to improve tumor selectivity, enhance internalization, overcome antigen escape, and expand the population of CRC patients eligible for targeted therapy. Emerging preclinical studies demonstrate encouraging anti-tumor activity for bispecific modalities in CRC, while early clinical trials are beginning to establish their translational potential. This review summarizes the current landscape of bsAbs and bsADCs in therapeutic development for CRC, highlighting key biological targets, engineering strategies, mechanisms of action, and clinical status. We also discuss the major challenges facing clinical translation and provide perspectives on future directions for bispecific therapies in CRC. Full article

Background and Objectives: Antibody–drug conjugates (ADCs) have become a major therapeutic platform in breast cancer and other solid tumors. Trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), and sacituzumab govitecan (SG) differ substantially in antibody target, linker, payload, drug-to-antibody ratio, and bystander effect, resulting in heterogeneous pulmonary and cardiac toxicity profiles. This narrative review critically compares interstitial lung disease (ILD)/pneumonitis and cardiotoxicity associated with these three agents, aiming to prevent inappropriate extrapolation of toxicity algorithms and to provide a practical, agent-specific framework for multidisciplinary care. Materials and Methods: A targeted narrative search of PubMed/MEDLINE, Google Scholar, ClinicalTrials.gov, regulatory product information, and oncology/cardio-oncology guidance was performed and updated on 24 August 2026. Priority was given to regulatory documents, pivotal trials, pooled safety analyses, real-world cohorts, systematic reviews, and multidisciplinary recommendations. Pharmacovigilance data and case reports were included only to characterize rare events. Results: T-DXd is associated with a clinically important ILD/pneumonitis risk (approximately 12–15% in pooled analyses), predominantly grade 1–2 but occasionally fatal, requiring proactive surveillance, immediate interruption for suspected disease, and grade-directed corticosteroid therapy. T-DM1 shows a low but established pneumonitis incidence of approximately 1%, with permanent discontinuation recommended upon diagnosis. SG-related pneumonitis is rare and incompletely defined, without a T-DXd-like surveillance mandate. Both T-DM1 and T-DXd retain trastuzumab-derived cardiac monitoring requirements; symptomatic heart failure remains uncommon, although protocol-defined LVEF declines appear more frequent with T-DXd. SG lacks an established cardiomyopathy signal. Conclusions: Cardiopulmonary toxicity of ADCs is agent-specific rather than a class effect. Monitoring intensity, diagnostic thresholds, and management pathways must be tailored to the individual drug, regimen, indication, dose, patient comorbidity, and prior therapy. Close collaboration among oncology, radiology, pulmonology, and cardio-oncology is essential to preserve both treatment efficacy and patient safety. Full article

Lung cancer is currently the most frequently diagnosed malignancy worldwide, accounting for approximately 12.4% of all cancers and, despite major advances in molecularly targeted therapies and immunotherapy, represents the leading cause of cancer-related mortality. In recent years, antibody–drug conjugates (ADCs) have emerged as a novel therapeutic strategy, combining the specificity of monoclonal antibodies with the potent cytotoxic activity of highly active payloads to selectively target tumor cells while limiting systemic toxicity. This narrative review summarizes the current role of ADCs in lung cancer, with particular focus on their structural components, mechanisms of action, and the biological features that determine treatment efficacy. We discuss the rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation. The principal mechanisms of primary and acquired resistance are also reviewed, including antigen modulation, altered intracellular trafficking, lysosomal dysfunction, drug efflux, tumor microenvironment-mediated immune suppression, and intratumor heterogeneity. In addition, we provide an overview of the safety profile of ADCs, highlighting the most clinically relevant adverse events and their underlying biological mechanisms. We also examine the evolving landscape of predictive biomarkers beyond antigen expression, including genomic, transcriptomic, proteomic, and liquid biopsy-based approaches, together with emerging spatial and single-cell technologies that may improve patient selection. Finally, we discuss future directions in the field, including novel payloads, next-generation linker technologies, bispecific ADCs, combination strategies, and personalized ADC development. Overall, ADCs are rapidly reshaping the therapeutic landscape of lung cancer. Continued optimization of drug design, biomarker-driven patient selection, and a deeper understanding of resistance mechanisms will be essential to fully realize their clinical potential. Full article

Urothelial carcinoma (UCC) remains a clinical challenge due to its high recurrence rate and aggressive advanced-stage behavior. Driven by a high tumor mutational burden and the consistent overexpression of surface antigens, including Nectin-4, Trop-2, and HER2, UCC has become a prime target for antibody-mediated therapies. Although both immune checkpoint inhibitors (ICIs) and antibody–drug conjugates (ADCs) show significant clinical efficacy, their rational combination further enhances antitumor activity via immunogenic cell death. However, therapeutic resistance and immune evasion still limit response durability in many patients. This review provides a comprehensive overview of the molecular principles, mechanisms of action, and clinical efficacy of antibody-based UCC therapies. Additionally, we analyze biomarkers for patient selection, the mechanisms underlying resistance development, and the rationale for ADC-ICI combinations. By evaluating current challenges and unmet needs, this review aims to clarify the evolving therapeutic landscape and suggest future directions for optimizing UCC treatment. Full article

Background: Amoxicillin–clavulanate (AC) is the antibiotic most frequently implicated in idiosyncratic drug-induced liver injury (DILI) worldwide, and it characteristically produces a cholestatic or mixed pattern in older adults. A predominantly hepatocellular presentation is distinctly less common in this age group, and reports from the Arabian Peninsula are scarce. Case presentation: A 66-year-old Saudi man developed painless, progressive jaundice after a seven-day course of oral AC (500/125 mg three times daily) prescribed for a thumb laceration. He described a similar self-limiting jaundice after the same antibiotic approximately five years earlier, an episode that was never investigated and had not been entered in his allergy record, so the drug was prescribed again unknowingly. Liver biochemistry, documented as normal four months earlier, showed alanine aminotransferase (ALT) peaking at 587 U/L (14.3 × the upper limit of normal, ULN) and aspartate aminotransferase at 335 U/L, with total bilirubin 249 µmol/L (11.9 × ULN) and a 69% conjugated fraction, whereas alkaline phosphatase (ALP) never exceeded 245 U/L (1.9 × ULN). The R-value at the ALT peak was 19.3 using the same-day ALP, and 7.6 even when the peak ALT is paired with the highest ALP recorded at any point in the illness; the pattern was therefore hepatocellular (R > 5) throughout the injury phase. Hy’s law criteria were met, although the international normalised ratio remained 1.0 and no encephalopathy developed. Peripheral eosinophilia (peak 1.05 × 10⁹/L) was documented. Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody and HIV serology were non-reactive; antinuclear, anti-smooth-muscle, anti-liver-kidney microsomal type 1 and antimitochondrial antibodies were negative and serum ceruloplasmin was normal; ultrasound with contrast-enhanced triphasic computed tomography excluded biliary obstruction and malignancy. Hepatitis A and E serology and cytomegalovirus/Epstein–Barr studies were unavailable at our institution, which we report as a limitation. AC was withdrawn and management was supportive. Liver biochemistry normalised completely over the following three months (ALT 25 U/L, ALP 103 U/L, and total bilirubin 22 µmol/L). Updated Roussel Uclaf Causality Assessment Method (RUCAM) scoring on the hepatocellular scale gave 7 points (probable); no credit was taken for the historical episode, since RUCAM requires documented enzyme re-elevation for a positive re-administration response. Conclusions: AC can cause hepatocellular, Hy’s-law-positive injury in older adults, not only the cholestatic phenotype emphasised in the literature. The decisive failure here was administrative rather than diagnostic: an adverse drug reaction that is never recorded will be repeated. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, with five-year survival below 5% for metastatic small cell lung cancer (SCLC) and below 10% for metastatic non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors have improved outcomes, but primary and acquired resistance, driven by tumor microenvironment immunosuppression, antigen heterogeneity, and T-cell exhaustion, leaves a substantial unmet need. T-cell engagers (TCEs), bispecific antibodies that redirect cytotoxic T-cells to tumor cells independent of MHC-I-restricted antigen presentation, offer a mechanistically distinct approach. Methods: We conducted a structured narrative review, without formal PRISMA methodology or meta-analytic pooling, of PubMed, Embase, and ClinicalTrials.gov through June 2026, supplemented by conference abstracts from ASCO, ESMO, AACR, and ATS, covering clinical, translational, and preclinical evidence for TCEs across established and emerging targets in thoracic malignancy. Results: Tarlatamab, a DLL3/CD3 bispecific TCE, received full FDA approval in November 2025 based on DeLLphi-304 data showing a median overall survival benefit of 13.6 versus 8.3 months over chemotherapy (HR 0.60; p < 0.001), establishing proof-of-concept for the TCE platform in lung cancer and NCCN Category 1 status in ES-SCLC. Beyond DLL3, an expanding pipeline of targets, including Claudin-18.2, TROP-2, FOLR1, CD70, and HER2, is under active TCE development; several of these antigens have independently validated tumor-selective expression through approved or late-stage antibody-drug conjugates (ADCs), providing target-level clinical de-risking for TCE development, though the two modalities have distinct requirements for antigen density and internalization that must be independently validated. Novel tri-specific constructs incorporating costimulatory domains and combination strategies with checkpoint inhibitors are in early clinical development. Conclusions: Tarlatamab approval validates the TCE platform in lung cancer, but overcoming TME-mediated resistance, antigen heterogeneity, and class-specific toxicities including cytokine release syndrome remains the central challenge. Rational TCE design, incorporating costimulatory signaling, antigen selection informed by parallel ADC validation data, and evidence-based combination strategies, offers the most credible path toward expanding this platform’s impact in metastatic lung cancer. Full article

Background/Objectives: Cervical cancer (CC) is currently one of the leading causes of cancer-related mortality worldwide. Patients with advanced, recurrent, or metastatic CC, for whom treatment options are limited, are particularly at risk. Tisotumab vedotin (TV) is a first-in-class antibody–drug conjugate targeting tissue factor (TF), representing a promising therapeutic breakthrough. This systematic review aims to comprehensively evaluate the clinical efficacy, safety profile, and therapeutic potential of TV, both as monotherapy and in combination regimens, in patients with advanced cervical cancer. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Embase databases, as well as on the ClinicalTrials.gov website, for prospective clinical trials (Phases I–III) in accordance with the PRISMA 2020 guidelines. The search focused on original articles and studies published between 2019 and 2026. Four key clinical trial programmes (innovaTV 201, 204, 205, and 301), involving 548 patients, were selected. Quality assessment was performed using the Cochrane RoB 2.0 tool and the NIH tool for assessing the quality of “before-and-after” studies. Results: Objective response rates (ORR) with TV ranged from 17.8% in monotherapy to 65.8% in combination regimens, confirming its efficacy in treatment. In randomised Phase III trials, the use of TV improved overall survival compared to standard chemotherapy. Adverse effects characteristic of TV are primarily ophthalmic complications, peripheral neuropathy, and hemorrhagic events. These were managed through pre-established prophylactic and monitoring protocols. Combination therapies increased therapeutic efficacy but also raised the incidence of grade ≥ 3 adverse events occurring during treatment. Conclusions: TV offers new hope by changing the treatment algorithm for cervical cancer. As a targeted therapy, it provides an effective alternative to conventional chemotherapy in previously treated patients. It also has the potential for use in first-line multi-drug treatment regimens. Strict adherence to safety protocols is essential to minimise toxicity and ensure treatment continuity. Full article

Gastrointestinal (GI) cancers represent a diverse group of malignancies that remain a major cause of cancer-related morbidity and mortality worldwide. Their management is increasingly complex, reflecting differences in tumor biology, anatomical location, stage, and molecular profile. In recent years, advances in molecular diagnostics, immunotherapy, and targeted treatment have moved clinical decision-making beyond a purely organ- and stage-based approach toward more individualized, biomarker-guided care. This narrative review summarizes established and emerging biological and targeted therapies used in esophageal, gastric and gastroesophageal junction, colorectal, pancreatic, hepatocellular, and biliary tract cancers. It focuses on immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4; HER2-directed monoclonal antibodies and antibody–drug conjugates; antiangiogenic and anti-EGFR therapies; and newer strategies involving CLDN18.2, FGFR2b, and tumor-agnostic alterations such as NTRK fusions. The review also considers the predictive biomarkers used to guide treatment selection and the growing integration of systemic therapy with surgery in neoadjuvant, perioperative, adjuvant, and conversion settings. However, clinical efficacy alone does not determine whether new treatments become part of routine practice. Regulatory approval, reimbursement, access to molecular testing, and the availability of specialized multidisciplinary care are equally important. The rapidly evolving treatment landscape for GI cancers therefore requires clinical decisions that account for tumor biology, anatomical resectability, molecular eligibility, expected benefit, treatment-related toxicity, and local access to therapy. Expanding access to comprehensive biomarker testing and effective molecularly guided treatments will be essential to translate progress in precision oncology into more personalized and equitable care for patients with GI cancers. Full article

Antibody–drug conjugates (ADCs) are structurally complex biopharmaceuticals whose quantitative characterization is often complicated by payload-related interferences and molecular heterogeneity. In this study, two complementary chromatographic methods based on reverse-phase ultra-high-performance liquid chromatography (RP-UHPLC) and size-exclusion ultra-performance liquid chromatography (SEC-UHPLC) coupled with diode array detection were developed and comparatively evaluated for quantitative and integrity assessment of Cetuximab (CET) in ADC formulations. The RP-UHPLC method, developed on a C8 stationary phase under denaturing conditions, showed linearity over the range 0.05–5 mg/mL (R² = 0.9979), with LOD and LOQ values of 10 and 40 μg/mL, respectively. The SEC-UHPLC method, optimized under native conditions on a Yarra SEC-3000 column, exhibited linearity within the 0.5–5 mg/mL range (R² = 0.9998), with LOD and LOQ values of 17 and 52 μg/mL, respectively. Both methods showed satisfactory accuracy, precision, and robustness according to a fit-for-purpose validation approach. Application to CET-based ADCs bearing different aminobisphosphonate payloads confirmed reliable quantification. RP-UHPLC enabled sensitive determination of antibody concentration, whereas SEC-UHPLC enabled assessment of monomeric integrity and sample heterogeneity under native conditions. Comparative analysis of aged ADC samples demonstrated that SEC-UHPLC revealed loss of structural integrity and sample heterogeneity that were not detectable by RP-UHPLC or direct UV spectrophotometry. The combined RP-UHPLC/SEC-UHPLC workflow provides a robust, accessible, and complementary platform for routine quantitative analysis and integrity assessment of ADC formulations. Full article

Antibody–drug conjugates (ADCs) have matured from a technically challenging concept into an established therapeutic platform across hematologic and solid malignancies. By linking a monoclonal antibody to a potent cytotoxic payload, ADCs seek to increase tumor-directed drug delivery while limiting systemic exposure; however, clinical performance depends on much more than target expression. Target accessibility, antigen density and heterogeneity, internalization, intracellular trafficking, linker stability, payload properties, drug-to-antibody ratio, bystander effect, tumor penetration, and host-tissue handling jointly shape efficacy and toxicity. This review provides a clinician-oriented assessment of the contemporary ADC landscape and the principal biologic and pharmacologic determinants of benefit. We discuss signature toxicities, including interstitial lung disease and ocular injury, and summarize evolving mechanisms of resistance and biomarker development. Particular emphasis is placed on three translational problems that are becoming increasingly important as ADCs move into earlier lines and overlapping disease settings: dose optimization beyond the maximum tolerated dose, sequencing across targets and payload classes, and biologically rational combination strategies. We also present a conceptual Sequential Tumor Attack Model as a hypothesis-generating framework for tumor-access priming, ADC-mediated cytotoxic injury, and immune amplification, while explicitly recognizing that the complete model has not been clinically validated. The future impact of ADCs will depend not only on next-generation constructs, but also on rigorous evidence for how these agents should be dosed, ordered, and combined in practice. Full article