免疫治疗背景下小细胞肺癌耐药机制及应对策略OA

Small cell lung cancer(SCLC)is a highly aggressive malignancy that is initially sensitive to chemotherapy and radiotherapy but is characterized by early relapse and poor prognosis.The introduction of immune checkpoint inhibitors has improved the treatment landscape for extensive-stage SCLC;however,the overall clinical benefit remains limited,and resist-ance to immunotherapy is almost inevitable.Accumulating evidence indicates that immunotherapy resistance in SCLC does not arise from the inactivation of a single immune path-way,but rather from the interplay of multiple mechanisms,in-cluding tumor-intrinsic immune inertia,an immunosuppressive tumor microenvironment,and impaired host systemic immune responsiveness.Molecular subtype heterogeneity,defective an-tigen presentation,epigenetic repression,and lineage plasticity establish the foundation of immune sensitivity,while suppres-sive myeloid cells,cancer-associated fibroblasts,and aberrant cytokine networks further attenuate effective antitumor immune responses.In this context,blockade of a single immune checkpoint is insufficient to achieve durable disease control.In re-cent years,mechanism-based combination strategies aimed at restoring tumor immunogenicity,remodeling the immunosup-pressive microenvironment,and actively directing effector immune responses have emerged.Notably,agents targeting DNA damage response pathways,metabolic reprogramming,as well as DLL3-targeted antibody-drug conjugates and T-cell engag-ers,have provided new opportunities to overcome immunotherapy resistance.Systematic integration of resistance mechanisms with biologically driven combination strategies may facilitate the transition of immunotherapy in SCLC toward greater precision and sustained clinical benefit.