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

J Thorac Dis. 2026 Aug 31;18(8):950. doi: 10.21037/jtd-2026-1704. Epub 2026 Aug 28.

ABSTRACT

BACKGROUND AND OBJECTIVE: Traditionally, two primary systems have been employed for staging small cell lung cancer (SCLC): the Veterans Administration Lung Study Group (VALG) system and the International Association for the Study of Lung Cancer (IASLC) tumor, node, metastasis (TNM) system. The term "limited disease" is defined differently: VALG characterizes it as disease encompassed within a single tolerable radiation field, while IASLC defines it as the lack of distant metastases (M0). Patients with N3 disease frequently satisfy VALG extensive-stage (ES) criteria while meeting IASLC limited-stage (LS) criteria, resulting in a notable staging discrepancy. Therefore, this review aims to clarify the clinical challenges posed by this staging overlap and provide insights for standardizing staging terminology and optimizing therapeutic decision-making in N3 SCLC.

METHODS: A narrative review utilizing a systematized search strategy was conducted. While strict adherence to PRISMA guidelines was not pursued because the extensive heterogeneity of the literature precluded a formal meta-analysis, rigorous search criteria were applied to minimize selection bias. Databases including PubMed, Web of Science, Embase, the Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched for literature from January 2000 to March 2026. Studies examining stage N3 SCLC, spatial metastatic burden, and definitional inconsistencies between the VALG and IASLC staging systems were analyzed to assess their effects on treatment dosimetry, systemic therapy, and survival outcomes.

KEY CONTENT AND FINDINGS: The staging overlap in N3 SCLC leads to heterogeneous clinical management depending on its spatial metastatic burden, and this highly variable cohort can be stratified into distinct prognostic subgroups based on the anatomical distribution (single-region vs. multi-region) of the involved lymph nodes.

CONCLUSIONS: These findings should guide clinical trial design and terminology. Clinical decision-making must transcend historical paradigms and technical constraints. Future strategies must incorporate spatial evaluations of metastatic burden alongside innovative multimodal tools, such as artificial intelligence (AI) and multi-omics, to facilitate tailored therapy for SCLC.

PMID:42724560 | PMC:PMC13559235 | DOI:10.21037/jtd-2026-1704

Gut. 2026 Sep 7:gutjnl-2025-337414. doi: 10.1136/gutjnl-2025-337414. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood.

OBJECTIVE: To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC.

DESIGN: We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens.

RESULTS: TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8⁺ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8⁺ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis.

CONCLUSION: Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

PMID:42705697 | DOI:10.1136/gutjnl-2025-337414

Gut. 2026 Sep 7:gutjnl-2025-337414. doi: 10.1136/gutjnl-2025-337414. Online ahead of print.

ABSTRACT

BACKGROUND: Neutrophils are increasingly recognised as immunosuppressive drivers of hepatocellular carcinoma (HCC), yet their persistence in the oxidative, lipid-rich tumour microenvironment remains poorly understood.

OBJECTIVE: To elucidate the metabolic and molecular programmes that enable tumour-associated neutrophils (TANs) to resist ferroptosis and sustain immunosuppression in HCC.

DESIGN: We employed human HCC samples, multiple murine HCC models, transcriptomic and lipidomic profiling, genetic loss-of-function systems and therapeutic interventions. Ferroptosis sensitivity, lipid metabolic rewiring and immunological consequences of TANs were systematically evaluated across models and validated in patient datasets and biospecimens.

RESULTS: TANs in human HCC and mouse models exhibit pronounced lipid accumulation and oxidative stress compared with peripheral neutrophils. Multi-omic profiling revealed that TANs are enriched for lipid-binding gene programmes and undergo rewiring towards sphingolipid and unsaturated fatty acid metabolism. We identified triggering receptor expressed on myeloid cells 2 (TREM2) as a key lipid-sensing receptor selectively expressed in TANs. Functional deletion of TREM2 reprogrammed the tumour immune microenvironment, restoring CD8⁺ T cell activity and suppressing HCC progression. Mechanistically, tumour-derived sphingosine-1-phosphate (S1P) activates TREM2, triggering nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcription of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby promoting ferroptosis resistance. TREM2 expression is transcriptionally induced by granulocyte-macrophage colony-stimulating factor-signal transducer and activator of transcription 3 (GM-CSF-STAT3) signalling. Genetic deletion of TREM2, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout of sphingosine kinase 1/2 (SPHK1/2) in tumour cells, or pharmacological inhibition of S1P synthesis disrupts this protective lipid-immune circuit, sensitises TANs to ferroptosis and restricts tumour growth. Therapeutically, a peptide-based TREM2 inhibitor reprogrammes TANs, restores CD8⁺ T cell function and enhances anti-programmed cell death protein 1 (PD-1) immunotherapy efficacy. Clinically, TREM2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in HCC tumours, correlate with SPHK1/2 expression and T cell dysfunction and associate with poor patient prognosis.

CONCLUSION: Our study uncovers the S1P-TREM2-NRF2 axis as a critical metabolic-immune circuit that preserves neutrophil survival and immunosuppressive function in HCC. Targeting this lipid-dependent ferroptosis resistance pathway offers a promising therapeutic strategy to overcome immunotherapy resistance in liver cancer.

PMID:42705697 | DOI:10.1136/gutjnl-2025-337414

Probiotics Antimicrob Proteins. 2026 May 23. doi: 10.1007/s12602-026-11062-2. Online ahead of print.

ABSTRACT

Autoimmune hepatitis (AIH) is a chronic progressive inflammatory liver disease with a rising global incidence. The treatment of AIH remains challenging because first-line drugs show limited efficacy and systemic side effects. Gut microbiota plays a crucial role in the pathogenesis of AIH, leading to growing interest in developing probiotic-based therapies. In this study, we used multi-omics analysis to investigate the therapeutic effects of a quadruple probiotic mixture (Probiotic-quad) consisting of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus in a well-established chronic AIH murine model. Our results showed that Probiotic-quad treatment significantly alleviated AIH progression, as evidenced by lower serum liver enzyme levels, ameliorated hepatic inflammatory infiltration and histopathological damage. Metagenomic sequencing results showed that gut dysbiosis in AIH mice was partially reversed after Probiotic-quad administration. Additionally, the integrity of the intestinal epithelial barrier was restored, accompanied by a reduction in serum lipopolysaccharide levels. Untargeted metabolomic and transcriptomic analysis revealed that Probiotic-quad treatment was linked to alterations in hepatic metabolism, including the citrate cycle and tryptophan metabolism, and was associated with reduced activation of the NF-κB and NOD-like receptor signaling pathways. These findings suggest that Probiotic-quad treatment ameliorates AIH severity and is potentially associated with changes in hepatic immune responses, metabolism, gut microbiota, and intestinal barrier function, highlighting its potential as an adjuvant therapy for AIH.

PMID:42176246 | DOI:10.1007/s12602-026-11062-2

Sci China Life Sci. 2026 Mar 16. doi: 10.1007/s11427-025-3273-6. Online ahead of print.

ABSTRACT

Phenotypic diversity of malignant cells within a tumor underlies intratumor heterogeneity (ITH), a key determinant of cancer metastasis and treatment failure. However, the molecular mechanisms driving this heterogeneity are poorly understood. Here, we curated and analyzed a cohort of 3' tag-based single-cell RNA-seq covering 12 common cancer types. We identified thousands of poly(A) site (PAS) peaks representing the 3' ends of previously unannotated transcripts, whose expression is widely associated with diverse malignant cellular states. By integrating multi-omics data, we characterized the expression patterns and epigenetic landscape of these unannotated PAS peak-associated transcripts (UPTs). The expression heterogeneity of UPTs was supported by multi-region sampling bulk RNA-seq data and recapitulated within cancer cell lines. As proof of principle validation, functional experiments confirmed that two noncoding UPTs promoted the proliferation and migration of lung cancer cells. Our results suggest that epigenetic activation of unannotated noncoding transcripts might represent a previously unrecognized mechanism contributing to transcriptomic ITH.

PMID:41870780 | DOI:10.1007/s11427-025-3273-6

Sci China Life Sci. 2026 Mar 16. doi: 10.1007/s11427-025-3273-6. Online ahead of print.

ABSTRACT

Phenotypic diversity of malignant cells within a tumor underlies intratumor heterogeneity (ITH), a key determinant of cancer metastasis and treatment failure. However, the molecular mechanisms driving this heterogeneity are poorly understood. Here, we curated and analyzed a cohort of 3' tag-based single-cell RNA-seq covering 12 common cancer types. We identified thousands of poly(A) site (PAS) peaks representing the 3' ends of previously unannotated transcripts, whose expression is widely associated with diverse malignant cellular states. By integrating multi-omics data, we characterized the expression patterns and epigenetic landscape of these unannotated PAS peak-associated transcripts (UPTs). The expression heterogeneity of UPTs was supported by multi-region sampling bulk RNA-seq data and recapitulated within cancer cell lines. As proof of principle validation, functional experiments confirmed that two noncoding UPTs promoted the proliferation and migration of lung cancer cells. Our results suggest that epigenetic activation of unannotated noncoding transcripts might represent a previously unrecognized mechanism contributing to transcriptomic ITH.

PMID:41870780 | DOI:10.1007/s11427-025-3273-6

Gastric Cancer. 2026 Mar 13. doi: 10.1007/s10120-026-01718-x. Online ahead of print.

ABSTRACT

BACKGROUND: 5-Fluorouracil (5-FU) remains a cornerstone of first-line chemotherapy for gastric cancer, yet the emergence of resistance severely compromises its clinical efficacy. Although ferroptosis suppression has been recognized as a pivotal mechanism of chemoresistance, the mitochondrial regulatory processes involved remain poorly understood.

METHODS: We integrated clinical specimen analysis, in vitro and in vivo functional assays, multi-omics profiling, and molecular docking to delineate the role of the mitochondrial oxidoreductase OXNAD1 in mediating 5-FU resistance in gastric cancer, and to assess the therapeutic potential of the natural polyphenol resveratrol as a chemosensitizing agent.

RESULTS: OXNAD1 was found to be significantly overexpressed in gastric cancer tissues and cell lines, correlating with unfavorable prognosis and enhanced 5-FU resistance. Mechanistically, OXNAD1 directly bound to and suppressed the ferroptosis driver PTGS2, thereby attenuating lipid peroxidation and mitochondrial damage, ultimately restraining ferroptosis and promoting drug resistance. Notably, resveratrol disrupted the OXNAD1-PTGS2 interaction by directly binding OXNAD1, reinstating ferroptotic activity, markedly enhancing the cytotoxic effect of 5-FU in resistant cells, and potentiating the antitumor efficacy of 5-FU in xenograft models.

CONCLUSION: The OXNAD1-PTGS2 axis constitutes a critical metabolic-cell death cross-regulatory pathway underlying 5-FU resistance in gastric cancer. Targeting this axis with resveratrol provides a promising combinatorial strategy to overcome chemoresistance.

PMID:41824193 | DOI:10.1007/s10120-026-01718-x