Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

BMC Med. 2026 Apr 8. doi: 10.1186/s12916-026-04833-9. Online ahead of print.

ABSTRACT

Immunosenescence, the age-related decline in immune function, plays a crucial role in the pathogenesis and progression of lung diseases, including chronic obstructive pulmonary disease, lung cancer, pulmonary fibrosis, asthma, and respiratory tract infections. This comprehensive review examines the hallmarks of immunosenescence, and illustrates the association between immunosenescence and the pathogenesis of lung diseases. In addition, we discuss current and emerging therapeutic strategies that have been evaluated in human clinical trials for targeting immunosenescence in lung diseases. Specifically, this review provides in-depth insights into the therapeutic strategies, including senolytics and senomorphics, immunotherapy, stem cell therapy, thymic rejuvenation, probiotics, and lifestyle. We also highlight the potential of personalized approaches integrating multi-omics data and artificial intelligence to guide biomarker-driven interventions, enabling truly personalized therapeutic strategies. Finally, this review underscores the imperative for rigorously designed clinical trials to develop and validate interventions that specifically target immunosenescence, with the ultimate goal of improving clinical outcomes for the aged population with lung diseases.

PMID:41952158 | DOI:10.1186/s12916-026-04833-9