Next-generation immune-engaging therapies in small cell lung cancer: Biology, translation and resistance

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid progression, early dissemination, and limited durability of conventional treatment responses. The incorporation of immune checkpoint inhibitors into first-line therapy has improved outcomes for selected patients, but the overall benefit remains modest, and most patients eventually develop disease progression. These limitations reflect the complex biology of SCLC, including phenotypic plasticity, deficient or heterogeneous antigen presentation, an immunosuppressive tumor microenvironment, and multiple mechanisms of immune escape. Recent advances in next-generation immunotherapy, particularly bispecific and trispecific T-cell engagers, tumor-directed antibodies, antibody-drug conjugates (ADCs), and other immune-engaging platforms, are creating new opportunities for therapeutic intervention. However, the biological determinants of response, treatment-related toxicity, and primary or acquired resistance remain incompletely understood. Integrating tumor biology with translational and early clinical evidence is therefore essential to guide the rational development of these approaches. This Research Topic aims to define how next-generation immune-engaging therapies can overcome immune escape and improve therapeutic activity in SCLC. We will highlight studies investigating the interaction between tumor-intrinsic features, antigen expression, immune-cell recruitment, and therapeutic response, with particular emphasis on bispecific and trispecific T-cell engagers, tumor-directed antibodies, and ADC-based strategies. We also seek to clarify the mechanisms underlying response heterogeneity, treatment resistance, and immune-related or T-cell engager-associated toxicities. By bringing together basic, translational, and early clinical research, this Research Topic will advance the development of biologically informed treatment strategies and identify priorities for the next generation of SCLC immunotherapy.To gather further insights into the tumor biology, immune mechanisms, and translational development of next-generation immune-engaging therapies in SCLC, we welcome articles addressing, but not limited to, the following themes:• Next-generation T-cell engagers: Preclinical, translational, and early clinical studies of bispecific and trispecific antibodies in SCLC.• Tumor-directed antibodies and ADCs: Antigen selection, mechanisms of action, immune modulation, therapeutic efficacy, and rational combinations with immunotherapy.• SCLC tumor–immune interactions: Tumor antigen expression, immune-cell infiltration, immunosuppressive microenvironments, immune evasion, and phenotypic plasticity.• Biomarkers of response: Predictive biomarkers based on tumor biology, antigen expression, immune composition, circulating factors, and spatial or single-cell analyses.• Mechanisms of resistance: Primary and acquired resistance to T-cell engagers, antibody-based therapies, ADCs, and immune checkpoint inhibitors.• Therapy-associated toxicities: Biological mechanisms, prevention, monitoring, and management of cytokine release syndrome, ICANS, dysgeusia, and other toxicities associated with immune-engaging therapies.• Translational development: Integration of preclinical models, pharmacodynamic studies, and early-phase clinical trials to accelerate therapeutic development.• Rational therapeutic combinations: Combination strategies involving immune checkpoint inhibitors, chemotherapy, radiotherapy, ADCs, or other immune-modulating agents.We welcome Original Research, Review, Mini-Review, and Perspective articles. Manuscripts focused primarily on case presentations, retrospective clinical outcomes, or non-cancerous diseases are outside the scope of this Research Topic.Please note: Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic. Topic editors: Tetsuhiko Asao, Sun Min Lim, Zhaohui Arter Source: https://www.frontiersin.org/research-topics/84687/next-generation-immune-engaging-therapies-in-small-cell-lung-cancer-biology-translation-and-resistance