Emerging Therapeutic Strategies in Small-Cell Lung Cancer: From Adaptive Resistance to Precision Therapy

Small-Cell Lung Cancer: Biology, Translational Science and Clinical Innovation

Small-cell lung cancer (SCLC) is widely considered one of the most aggressive human malignancies, characterized by development of rapid metastases and eventual resistance to platinum chemotherapy and immunotherapy. For decades, despite rigorous scientific investigation and well-established mouse models providing a basis for mechanistic understanding, there were limited therapeutic advances for SCLC. The past decade has seen reinvigoration of drug development for SCLC as well as US Food and Drug Administration (FDA) approval of tarlatamab, a bispecific T-cell engager with unprecedented survival advantage in this recalcitrant disease. Multiple other promising clinical trials in the first and later-line settings are underway that seek to challenge standards of first-line chemoimmunotherapy, investigate combination treatments in the later line, and introduce T-cell engagers earlier in treatment. This review provides a comprehensive primer on the biology and molecular landscape of SCLC, in the context of how both shape ongoing investigational strategies. A broad overview of established multidisciplinary management of both limited-stage and extensive-stage SCLC is discussed to provide understanding of how the next decade is likely to bring significant clinical gains as emerging therapeutics seek to redefine the management of SCLC and build upon novel advances.

Beyond conventional therapies: the evolution of targeted agents and immunotherapies in triple-negative breast cancer.

Biomarker-Driven Insights into Immune Checkpoint Inhibitor Therapy in Small-Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options, and the integration of immune checkpoint inhibitors (ICIs) into treatment regimens has reshaped the therapeutic landscape. However, challenges such as rapid resistance and lack of effective predictive biomarkers remain. This review highlights the pivotal roles of biomarkers in SCLC, underscoring their contributions to treatment resistance across tumor-intrinsic mechanisms, immune landscape of the tumor microenvironment (TME) and systemic host factors. Tumor-intrinsic features, including molecular subtypes, genetic alterations such as TP53 and RB1 mutations, and tumor mutation burden (TMB), have shown varying associations with ICI efficacy. Notably, the SCLC-I (inflamed) molecular subtype appears more responsive to immunotherapy. Within the TME, programmed cell death ligand 1 expression, tumor-infiltrating lymphocytes (TILs), regulatory T cells, myeloid-derived suppressor cells, and tissue-associated cytokines and chemokines contribute to immune modulation. High CD8+ TILs are linked to better outcomes, while increased immunosuppressive populations often suppress anti-tumor response. Systemic factors, encompassing both tumor-derived (ctDNA, CTCs, tumor-derived EVs) and host-derived (circulating immune cell phenotypes, MHC expression, immune profile, baseline clinical characteristics) components, provide valuable insights into treatment response and prognosis. Further research is needed to validate biomarkers and investigate combination approaches to overcome resistance, offering hope for improved patient outcomes in SCLC.

Harnessing immunity against breast cancer: from checkpoints to cell therapies

Breast cancer (BC) remains the leading cause of cancer-related mortality and a major contributor to disease burden among women worldwide. Although PD‑1/PD‑L1‑targeting immune checkpoint inhibitors have become a standard treatment for certain triple‑negative breast cancer subgroups, their use across the broader BC population is limited by intrinsic resistance, an immunosuppressive tumor microenvironment (TME), and treatment‑related adverse effects. The present review offers a comprehensive synthesis of the immunotherapeutic paradigm in BC, spanning ICIs, adoptive cellular therapies (CAR-T, CAR-NK, CAR-M, TIL, TCR-T, and CIK cells), and emerging immune modulators. We critically evaluate pivotal clinical trials, discuss cross-cutting challenges—including biomarker development, therapy resistance, and the practical limitations of cellular products—and highlight rational combinatorial strategies. By contrasting the translational readiness of diverse modalities and outlining a framework for personalized therapy, this review aims to inform future research and clinical practice in harnessing immunity against BC.

Advanced and underlying therapeutic strategies in transformed small cell lung cancer

Transformed small-cell lung cancer (T-SCLC) is a clinically important form of histologic transformation and a mechanism of acquired resistance in non-small-cell lung cancer (NSCLC). It is associated with poor prognosis, with a median overall survival of only about 9–13 months. This review summarizes recent advances in the mechanisms, diagnosis, monitoring, and treatment of T-SCLC. Repeat biopsy remains the gold standard for confirming histologic transformation, whereas molecular profiling and liquid biopsy may facilitate early detection and longitudinal disease monitoring. Platinum-etoposide remains the most commonly used clinical standard after transformation, but its benefit is typically transient and durable disease control remains uncommon. Continuation of EGFR tyrosine kinase inhibitors combined with chemotherapy may prolong progression-free survival in selected patients but has not consistently improved overall survival. Anti-angiogenic therapy, particularly anlotinib, and chemo-immunotherapy have shown encouraging activity in selected patients, while emerging strategies targeting DLL3 , MYC , SOX2 , and epigenetic regulators may broaden the therapeutic landscape. Prospective studies integrating repeat tissue sampling, comprehensive genomic profiling, biomarker-guided patient stratification, pharmacogenomics, functional drug-sensitivity testing where feasible, and integrated multi-omics approaches are needed to advance molecularly guided and individualized treatment for T-SCLC.

Antibody–Drug Conjugates in Lung Cancer: Promise, Progress, and Persistent Challenges

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 are discussed.