Therapy-induced methionine competition in bladder cancer: MAT2A-SAM axis remodeling as a metabolic immune checkpoint
- 1Department of Urology, The First Hospital of China Medical University
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.
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BibTeX
@article{zhang2026therapyinduced,
title = {{Therapy-induced methionine competition in bladder cancer: MAT2A-SAM axis remodeling as a metabolic immune checkpoint}},
author = {Chengyuan Zhang and Zhe Zhang and Jianbin Bi},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1965813},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1965813/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Therapy-induced methionine competition in bladder cancer: MAT2A-SAM axis remodeling as a metabolic immune checkpoint
AU - Chengyuan Zhang
AU - Zhe Zhang
AU - Jianbin Bi
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1965813
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1965813/full
AB - 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.
SN - 1664-3224
ER -