Nat Commun. 2026 Mar 23. doi: 10.1038/s41467-026-70798-1. Online ahead of print.

ABSTRACT

Glioblastoma (GBM) remains a lethal brain tumor due to therapy resistance. While autophagy contributes to temozolomide (TMZ) resistance, its regulation is incompletely understood. This study investigates the role of replication factor RFC4, which is associated with poor prognosis and TMZ resistance in GBM. Multi-omics analyses and molecular experiments reveal that TMZ-induced chromatin accessibility enables transcription factor YY1 to bind the RFC4 promoter and upregulate its expression. RFC4, in turn, stabilizes the kinase STK38, which is essential for autophagosome formation. The RFC4-STK38 interaction facilitates BECN1 recruitment, thereby activating autophagy. Phosphorylation of STK38 at T444 stabilizes this complex, whereas a phospho-deficient mutant impairs autophagy. In vivo, RFC4 overexpression confers TMZ resistance, reversible by autophagy inhibition. Thus, our findings identify the RFC4-STK38-BECN1 axis as a mechanism underlying TMZ resistance and a potential target for precision therapy in GBM.

PMID:41872171 | DOI:10.1038/s41467-026-70798-1

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

Clin Cancer Res. 2026 Mar 18. doi: 10.1158/1078-0432.CCR-25-4153. Online ahead of print.

ABSTRACT

PURPOSE: Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear.

EXPERIMENTAL DESIGN: This multicenter retrospective and prospective study included mNSCLC patients receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into <1 Gy, 1-3 Gy, and >3 Gy groups and treatment outcomes were compared. The blood and fecal samples were subjected to multi-omics profiling.

RESULTS: g>309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1-3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months) (P < 0.01), which was consistent across subgroups. Compared with 1-3 Gy, SIMRD >3 Gy (Hazard ratio [HR] = 4.87, P < 0.001) and <1 Gy (HR = 1.85, P < 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1-3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1-3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells.

CONCLUSIONS: ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1-3 Gy range, likely through modulation of the gut microbiota-metabolite-immune axis.

PMID:41849236 | DOI:10.1158/1078-0432.CCR-25-4153