bims-necame 2026-04-19 papers

Cell Rep Med. 2026 Apr 10. pii: S2666-3791(26)00158-8. [Epub ahead of print] 102741

Spatial multi-omics unveils the monoclonal origin, neuroendocrine plasticity, and microenvironment niches in combined small-cell lung cancer.

Zhuo Wang, Qing Luo, Jie Wu, Li Lu, Wenjie Ding, Yichun Zhao, Yongfeng Yu, Ruoran Qiu, Ling Zhu, Xinxing Ouyang, Wendi Xuzhang, Shun Lu, Wei Wei, Qihui Shi, Ziming Li.

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.

Keywords: LUAD-to-SCLC transdifferentiation; ST; TME; WES; cSCLC; combined small-cell lung cancer; single-nucleus RNA sequencing; snRNA-seq; spatial transcriptomics; spatially resolved whole-exome sequencing; tumor microenvironment

DOI: https://doi.org/10.1016/j.xcrm.2026.102741

Biotechnol J. 2026 Apr;21(4): e70228

Multi-omics Analysis Reveals the Correlation of Gut Microbiota and Metabolites With Thalidomide Treatment for Chemotherapy-Induced Nausea and Vomiting in Small Cell Lung Cancer.

Qiang-Guo Sun, Dan Zang, Yu Xin, Jia Cui, Xu Han, Jun Chen.

Small cell lung cancer (SCLC) is a highly aggressive malignancy, and chemotherapy frequently causes nausea and vomiting, which can impair treatment tolerance. Because thalidomide (THD) has shown potential clinical benefit in alleviating nausea and anorexia, we investigated whether its effects might be associated with changes in gut microbial composition and metabolite profiles. Fecal samples were collected from patients with SCLC and categorized into THD-treated and control groups. Metagenomic sequencing and nontargeted metabolomic profiling were performed to characterize microbial composition and metabolic signatures. THD treatment was also associated with higher microbial alpha diversity and increased abundance of genera such as Eubacterium and Prevotella. Metabolomic analysis identified several differential metabolites, including hydrogenated MDI, becocalcidiol, β-octylglucoside, and azelaic acid. Collectively, these findings suggest that the gut microbiota-metabolite axis may be associated with the potential effects of THD on CINV and anorexia in patients with SCLC. The identified microbial taxa and metabolites may serve as candidate biomarkers or potential therapeutic targets, although further validation in larger studies is necessary.

Keywords: gut microbiota; metabolites; small cell lung cancer; thalidomide

DOI: https://doi.org/10.1002/biot.70228

bioRxiv. 2026 Apr 08. pii: 2026.04.02.715020. [Epub ahead of print]

Transcription Factor Subtype Governs Response and Resistance to DLL3-Directed T-Cell Engagement in Small Cell Lung Cancer.

Although small cell lung cancer (SCLC) comprises transcription factor (TF)-defined molecular subtypes (ASCL1, NEUROD1, POU2F3), the extent to which these subtypes predict response to clinically effective therapy in patients-and whether therapy can select for subtype switching-remains unknown. The recent approval of the DLL3×CD3 bispecific T-cell engager tarlatamab represents one of the first meaningful advances in relapsed small cell lung cancer (SCLC) in decades, yet responses remain heterogeneous and resistance is inevitable. Here, we inferred SCLC gene expression from circulating chromatin in prospectively collected patient plasma (46 patients; 167 samples), enabling interrogation of response and acquired resistance to tarlatamab. Parallel development of the first immunocompetent syngeneic mouse model to study tarlatamab response and resistance enabled functional validation. Across species, findings converged on a central principle: TF subtype governs both initial response and acquired resistance. Therapeutic response was significantly associated with ASCL1-subtype tumors, whereas NEUROD1-subtype tumors exhibited inferior responses and POU2F3-subtype tumors were uniformly resistant, consistent with DLL3 being a direct ASCL1 transcriptional target and most highly expressed in ASCL1-positive tumors. Strikingly, one mode of acquired resistance revealed therapeutic selection for a NEUROD1-high state with concomitant DLL3 downregulation. Other resistant tumors exhibited enrichment of regulatory and exhausted T-cell programs, highlighting tarlatamab's dual-targeting mechanism of action. Together, these results reveal that tarlatamab exerts selective pressure against ASCL1-driven lineages, facilitating resistance through loss of an antigen intrinsically linked to that state. These findings underscore the clinical relevance of TF-defined molecular subtypes in human SCLC. More broadly, they highlight the power of integrating longitudinal in vivo plasma transcriptional profiling from patient plasma with functional mouse modeling to uncover clinical and biological mechanisms of response and resistance to cell-surface-targeted therapies.

DOI: https://doi.org/10.64898/2026.04.02.715020

Nat Commun. 2026 Apr 12. pii: 3435. [Epub ahead of print]17(1):

Differential KEAP1/NRF2 mediated signaling widens the therapeutic window of redox-targeting drugs in SCLC therapy.

Small cell lung cancer (SCLC) patients frequently experience a remarkable response to first-line therapy. Follow up maintenance treatments aim to control residual tumor cells, but generally fail due to cross-resistance, inefficient targeting of tumor vulnerabilities, or dose-limiting toxicity, resulting in relapse and disease progression. Here we show that SCLC cells, similar to their cells of origin, pulmonary neuroendocrine cells, exhibit low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, regardless of their molecular subtype or resistance to first-line therapy. Importantly, unlike non-cancerous cells, SCLC cells cannot adapt to drug-induced ROS stress due to the suppression of ROS defense mechanisms by multiple layers of gene regulation. By exploiting this difference in oxidative stress management, we safely increase the therapeutic dose of TXNRD1 inhibitors in vivo by pharmacological activation of the NRF2 stress response pathway. This results in improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors for maintenance therapy in SCLC.

DOI: https://doi.org/10.1038/s41467-026-71608-4

J Immunother Cancer. 2026 Apr 16. pii: e013867. [Epub ahead of print]14(4):

Single-cell and spatial transcriptomics reveal that the CXCL12-CXCR4 axis drives the immune-desert phenotype in small cell lung cancer by recruiting immunosuppressive CXCR4+ neutrophils and S100A8+ monocytes.

Peng Zeng, Hai-Feng Li, Wen-Bin Shu, Jing Zhang, Tian-Cheng Zhao, Jun-Wen Hu, Jun-Fu Wang, Cheng Wang, Qing-Yun Lu, Jia-Hui Yang, Yan-Li An, Rong Chen.

BACKGROUND: Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited responses to immunotherapy, largely due to its uniquely immunosuppressive tumor microenvironment (TME). However, the molecular mechanisms driving this phenotype remain incompletely understood.
METHODS: We integrated single-cell RNA sequencing and Xenium in situ spatial transcriptomics to analyze the immune microenvironment of five SCLC and four non-small cell lung cancer (NSCLC) samples. Multiplex immunofluorescence was used to validate cell types and gene expression in the same tissue specimens, and animal models were employed to verify the key mechanistic pathway.
RESULTS: SCLC displayed a distinct immune landscape compared with NSCLC, with increased infiltration of C-X-C motif chemokine receptor 4 (CXCR4)+ neutrophils (via neutrophil extracellular traps) and S100A8+ monocytes (toward an M2-like phenotype), and reduced CD8+ T-cell infiltration. Malignant epithelial cells in SCLC highly expressed CXCR4, regulated by transcription factors ISL LIM homeobox 1 and distal-less homeobox 5, which promoted immunosuppression. The C-X-C motif chemokine ligand 12 (CXCL12)-CXCR4 axis mediated competitive inhibition, impairing T-cell recruitment while enhancing neutrophil accumulation. Monocytes in SCLC shifted toward an M2-like phenotype, weakening antigen presentation. Xenium spatial transcriptomics confirmed colocalization of CXCR4+ neutrophils and S100A8+ monocytes with tumor cells at the tumor-normal interface, while CD8+ T cells were spatially segregated. In vivo experiments showed that CXCR4 inhibition reduced SCLC tumor growth, decreased immunosuppressive cell infiltration, and enhanced CD8+ T-cell accumulation.
CONCLUSIONS: The CXCL12-CXCR4 axis, together with immunosuppressive CXCR4+ neutrophils and S100A8+ monocytes, is a key driver of the immune-desert phenotype in SCLC. Targeting this axis holds promise as a therapeutic strategy to remodel the immunosuppressive TME and improve the efficacy of immunotherapy for SCLC.

Keywords: Immunosuppression; Immunotherapy; Lung Cancer; Monocyte; Neutrophil

DOI: https://doi.org/10.1136/jitc-2025-013867