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

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.