Targeting Tex10 Overcomes Oxaliplatin Resistance by Competitively Disrupting the Non-Canonical BAF Complex in Colorectal Cancer.

Although a small subset of colorectal cancer (CRC) patients benefit from immunotherapy, oxaliplatin (OXA)-based chemotherapy remains the first-line treatment. However, the widespread development of OXA resistance poses a major clinical challenge, and the underlying molecular mechanisms remain incompletely understood. In this study, we found that Tex10 deficiency markedly enhances OXA sensitivity in CRC cells by inducing cytostatic autophagy in xenograft and patient-derived organoid models. Tex10 -/- mice exhibit markedly reduced tumor numbers and decreased p62 levels in inflammation-induced CRC. Mechanistically, we determined that Tex10 competitively binds BRD9, thereby disrupting the BRD9-BRG1 interaction within the non-canonical BAF (ncBAF) complex, which suppresses AMBRA1 transcription and ULK1 ubiquitination to inhibit autophagy. Furthermore, in silico screening identified gemcitabine (GEM) as a potent Tex10 inhibitor. GEM directly binds to the N268 residue of Tex10, reducing Tex10 abundance and unleashing autophagy. This, in turn facilitates further lysosomal degradation of Tex10, forming a potent positive-feedback loop to overcome OXA resistance. In addition, Tex10 deletion enhances the antitumor efficacy of immunotherapy by inhibiting lysosomal degradation of PD-L1. Collectively, this study uncovers a previously unrecognized antitumor mechanism of GEM and identifies Tex10 as a promising therapeutic target for overcoming OXA resistance and potentiating immunotherapy in CRC.