811 Background: Bladder cancer shows high recurrence and limited benefit from immune-checkpoint blockade. Tumor metabolic reprogramming reshapes nutrient availability, thereby constraining T-cell function. Methionine metabolism, which generates the universal methyl donor S-adenosylmethionine (SAM), supports both tumor growth and T-cell epigenetic activity. The enzyme methionine adenosyltransferase 2A (MAT2A) catalyzes this step, but how tumor-intrinsic MAT2A influences antitumor immunity remains unknown. Methods: We integrated multi-omics analyses (RNA-seq, scRNA-seq, ChIP-seq) with CRISPR/Cas9 editing, metabolite quantification, and orthotopic mouse models. Patient cohorts were evaluated by immunohistochemistry and survival analysis. Functional studies combined MAT2A perturbation, SAM supplementation, and cisplatin treatment to examine metabolic competition, ER-stress signaling, and immune-checkpoint regulation in CD8⁺ T cells. Results: MAT2A was markedly upregulated in bladder cancer and independently predicted poor survival (HR = 3. 52, p < 0. 001). Cisplatin activated NRF2, which bound antioxidant-response elements in the MAT2A promoter and induced transcription. Tumor MAT2A consumed methionine and depleted SAM in the tumor microenvironment (−51% vs plasma), reducing the SAM/SAH ratio in neighboring CD8⁺ T cells and impairing IFN-γ secretion. SAM deficiency triggered PERK–eIF2α–CHOP activation, and CHOP bound PDCD1 and CTLA4 promoters, upregulating immune-checkpoint genes. CHOP deletion or PERK inhibition restored cytokine release. In vitro, SAM promoted tumor proliferation, yet in immunocompetent mice it enhanced CD8⁺ T-cell infiltration and effector activity. Combining SAM with cisplatin reduced tumor volume by 57% and prolonged survival (p < 0. 01). Human specimens confirmed positive correlations among MAT2A, CHOP, and PD-1 expression (r = 0. 72) and poor prognosis in MAT2Aʰigh/CHOPʰigh tumors. Conclusions: Tumor-intrinsic MAT2A reprograms methionine metabolism to deprive T cells of SAM, activating CHOP-dependent transcription of immune checkpoints and driving exhaustion. Targeting the MAT2A–SAM–CHOP axis or replenishing SAM restores T-cell function and enhances chemotherapy efficacy, revealing a metabolic checkpoint that links nutrient competition to immune escape in bladder cancer.
Zhang et al. (Sun,) studied this question.