5-FU chemotherapy induces functional CD7⁺ and IL7R⁺ CTLs infiltration to suppress colorectal tumor progression.

Authors

Yanmin Wu, Yan Li, Xufeng Yao, Yiyang Pan, Linlin Chen, Jian Zhang, Boyu Luo, Yue Teng, Mingqing Zhang, Chunwan Lu

Published in

Science China. Life sciences. Jul 16, 2026. Epub Jul 16, 2026.

Abstract

5-Fluorouracil (5-FU) is the cornerstone of chemotherapy for patients with advanced colorectal cancer. 5-FU acts primarily by inhibiting thymidylate synthase to prevent DNA and RNA synthesis, causing apoptosis in rapidly dividing cancer cells. Emerging literature indicates that 5-FU also suppresses tumor development by activating tumor-reactive T cells. However, the mechanism underlying 5-FU function in T cell activation in human colorectal cancer remains incompletely understood. In a comparative screening of human colorectal tumor tissues, we found that the levels of CD7⁺ cytotoxic T lymphocytes (CTLs) and IL7R⁺ CTLs subsets were significantly lower in human colorectal tumor tissues compared to matched adjacent nonneoplastic colon tissues. As expected, 5-FU therapy effectively suppressed colorectal tumor growth and enhanced total CTLs tumor infiltration in tumor-bearing mice. Analysis of tumor-infiltrating CTLs revealed that 5-FU therapy induced CD7⁺ and IL7R⁺ CTLs differentiation in the mouse colorectal tumor microenvironment. Mechanistically, p53 regulates CD7 and IL7R expression in CTLs by directly binding to the hCD7 and hCD127 promoters, respectively. Functionally, IL7R⁺CD8⁺ T cells exhibited improved cytotoxicity with elevated expression of T cell effector genes both in vivo and ex vivo in the mouse colorectal tumor microenvironment. More importantly, 5-FU therapy remarkably promoted CD7⁺ and IL7R⁺ CTLs tumor infiltration in colorectal cancer patients, as well as facilitated the infiltration of IL7R⁺ CTLs subsets in colorectal tumor-bearing mice. Overall, our findings determine that colon cancer suppresses the infiltration of CD7⁺ or IL7R⁺ CTLs into tumor microenvironment as a mechanism of immune evasion. 5-FU therapy represses colon cancer progression at least in part through activating p53 to foster CD7⁺ and IL7R⁺ CTLs tumor infiltration, thus proposing a new perspective for the anti-tumor mechanism of 5-FU and a novel, promising therapeutic route by expanding CD7⁺ and IL7R⁺ CTLs to improve the response to 5-FU chemotherapy.

PMID:
42469575
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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