Work

Therapy-induced methionine competition in bladder cancer: MAT2A-SAM axis remodeling as a metabolic immune checkpoint

Year: 2026

Type: article

Abstract: Bladder cancer is increasingly treated with platinum chemotherapy, immune checkpoint blockade, and antibody-drug conjugates, but treatment resistance remains common. Methionine connects nutrient availability with S-adenosylmethionine (SAM) production, methylation, redox homeostasis, and lymphocyte function. In cisplatin-resistant tumor cells, MAT2A stabilization sustains a SAM-dependent program of stem-like renewal and drug resistance. Concurrently, increased SLC7A6-associated methionine uptake can create a tumor methionine sink that lowers methionine and SAM in CD8+ T cells, weakens H3K79me2-STAT5 signaling, and impairs effector function. Separately, methionine-sensitive YTHDF1 signaling suppresses RIG-I-dependent innate sensing and increases PD-L1 translation. A layered metabolic immune checkpoint is proposed to explain how these convergent but non-equivalent mechanisms link treatment-selected tumor fitness, nutrient competition, and reduced immune visibility. The framework exposes a context-dependent therapeutic paradox: methionine restriction may weaken tumor adaptation but compromise T-cell fitness, whereas SAM restoration may support antitumor immunity while also fueling malignant cells. Therefore, treatment-state biomarkers should guide compartment-selective targeting and intervention timing.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1965813

Authors: Chengyuan Zhang, Zhe Zhang, Jianbin Bi

Institution: First Hospital of China Medical University

Language: English

Topic: Cancer Immunotherapy and Biomarkers

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801