Front Med (Lausanne). 2026 Aug 27;13:1865050. doi: 10.3389/fmed.2026.1865050. eCollection 2026.

ABSTRACT

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.

PMID:42724635 | PMC:PMC13560167 | DOI:10.3389/fmed.2026.1865050

Front Med (Lausanne). 2026 Aug 27;13:1865050. doi: 10.3389/fmed.2026.1865050. eCollection 2026.

ABSTRACT

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.

PMID:42724635 | PMC:PMC13560167 | DOI:10.3389/fmed.2026.1865050

Signal Transduct Target Ther. 2026 Sep 4;11(1):363. doi: 10.1038/s41392-026-02936-6.

ABSTRACT

Metabolic reprogramming forms the foundation of immune effector functions and the regulation of inflammation. As a pivotal node connecting the tricarboxylic acid cycle to immune signaling, the IRG1/ACOD1 and itaconate axes play a central role in coordinating inflammatory tone and redox balance. Itaconate, generated through the decarboxylation of cis aconitate, acts as an immunometabolic brake that engages multiple regulatory pathways to sustain the dynamic equilibrium between inflammation and tissue homeostasis. Across a broad spectrum of pathological conditions, including infectious diseases, metabolic disorders, ischemia‒reperfusion injury, neurodegenerative diseases, autoimmune disorders, and cancers, itaconate and its derivatives generally exert anti-inflammatory and cytoprotective effects. However, within specific microenvironments, these molecules may also be exploited by pathogens to evade immune clearance or promote immunosuppressive and protumorigenic responses. Future studies should further elucidate tissue- and lineage-specific functions, define bidirectional regulatory mechanisms, and optimize the pharmacokinetic properties of itaconate derivatives. With the advancement of multiomics integration, systems immunology, rational drug design, and engineered itaconate delivery technologies, the IRG1/ACOD1-itaconate axis and derivative-based therapeutic strategies are poised to emerge as key metabolic checkpoints and therapeutic targets in inflammatory-, metabolic-, immune-, and cancer-related diseases.

PMID:42693110 | PMC:PMC13542262 | DOI:10.1038/s41392-026-02936-6