Dietary Methionine Restriction Primes T Cell Metabolism for Activation and Tumor Inhibition and Enhances the Efficacy of Immune Checkpoint Blockade

Authors

• Xiaoqing Qing
• Binita Chakraborty
• Panpan Liu
• Sandeep Artham
• Patrick K Juras
• Dongyin Guan
• Kristen E Pauken
• Ching-Yi Chang
• Xia Gao

Language

English

Publication Date

9-23-2025

Journal

bioRxiv

DOI

10.1101/2025.09.18.676961

PMID

41040376

PMCID

PMC12485808

PubMedCentral® Posted Date

9-23-2025

PubMedCentral® Full Text Version

Pre-Print

Abstract

The proliferation of many cancer cells is methionine dependent and dietary methionine restriction (MR) has shown anti-tumor effects in a wide variety of immunodeficiency preclinical models. Yet, whether MR exerts an anti-tumor effect in the presence of an immune-competent background remains inconclusive. Accumulating evidence has shown an essential role of methionine in immune cell differentiation and function. Thus, competition for methionine between tumor cells and immune cells in the tumor microenvironment may drive tumor growth and tumor response to therapy. Here, we aim to define the impact of MR on tumor growth and associated immunity. We first assessed the effect of MR in a series of immunocompetent mouse models of melanoma, colorectal cancer, breast cancer, and lung. MR led to a broad tumor inhibition effect across these models and such tumor inhibition was not sex-or genetic background-dependent but appears to be fully or partially immune-dependent. Through flow cytometry analysis, we found a consistent increase in intratumoral activated CD8 + T cells across different tumor models and depletion of CD8 + T cells partially or completely reversed MR-induced tumor inhibition in a model dependent manner. Interestingly in young healthy non-tumor-bearing mice, MR increased spleen CD3 + and CD8 + T cell populations. Metabolomics and RNAseq analysis of spleen-derived CD8 + T cells revealed significant increase in purine metabolism and amino acid metabolism and that are in line with the metabolic feature of activated T cells. Furthermore, MR improved the efficacy of anti-PD1 immune checkpoint blockade. Together, MR primes T cell metabolism for its anti-tumor effect and improves the efficacy of anti-PD1 checkpoint blockade.

Published Open-Access

yes

Recommended Citation

Qing, Xiaoqing; Chakraborty, Binita; Liu, Panpan; et al., "Dietary Methionine Restriction Primes T Cell Metabolism for Activation and Tumor Inhibition and Enhances the Efficacy of Immune Checkpoint Blockade" (2025). Faculty, Staff and Students Publications. 8042.
https://digitalcommons.library.tmc.edu/baylor_docs/8042