SPP1⁺ TAMs drive colorectal tumorigenesis through an ARG2-orchestrated metabolic-immune crosstalk.

Authors

Linhong Song, Tingting Yan, Shi-Yuan Lu, Tianying Tong, Zhenyu Wang, Cheng-Bei Zhou, Zi-Yan Zhuang, Yile Xie, Xiaoxu Leng, Chenyi Zhang, Youli Chen, Wei-Qi Gu, Yun Cui, Zi-Zhen Zhang, Jinxian Chen, Haoyan Chen, Jie Hong, Huimin Chen, Ying-Xuan Chen, Jing-Yuan Fang

Published in

Cancer letters. Pages 218890. Oct 13, 2026. Epub Oct 13, 2026.

Abstract

Rising incidence of colorectal cancer (CRC) and limited therapeutic options highlight the urgent need to define the drivers of its progression. The SPP1⁺ tumor-associated macrophage (TAM) subset identified by single-cell transcriptomics is a functionally dominant population that extends beyond the classical M1/M2 paradigm. Here, we dissected the molecular mechanisms by which SPP1⁺ TAMs reprogram tumor progression and determined whether the gut microbiota regulates this process in colorectal cancer. Using a multi-platform strategy integrating clinical specimens, murine models and CRC cell lines, we found that SPP1⁺ TAMs increase progressively during CRC evolution and exhibit crosstalk with malignant epithelial cells, and their abundance is associated with adverse clinical outcome. Integrative analysis reveals a significant positive correlation between SPP1 and ARG2 expression. Further, TAM-derived SPP1 engages CD44 on CRC cells to induce ARG2 expression. Mechanistically, ARG2 facilitates the interaction between USP10 and c-Myc to deubiquitinate and stabilize c-Myc, which transactivates the glycolytic enzyme HK2, driving Warburg metabolism that fuels CRC cell proliferation. Moreover, ARG2 secreted by CRC cells is internalized by TAMs, which reciprocally upregulates SPP1, creating a feed-forward loop that drives a pro-tumorigenic microenvironment. Notably, Bifidobacterium longum downregulates CD44 expression on tumor cells, thereby disrupting the SPP1-ARG2 axis and attenuating CRC progression. These findings identify the SPP1-ARG2 circuit as a therapeutic target and propose B. longum as a microbiome-derived precision adjuvant therapy for CRC suppression.

PMID:
42869126
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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