Abstract
Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide. Regulatory T cells (Tregs) are key immune regulators that inhibit anti-tumor immune responses by suppressing effector T-cell functions and fostering an immunosuppressive tumor microenvironment. Despite epidemiological evidence showing an inverse association between milk consumption and CRC risk, the underlying mechanisms remain unclear. While milk-derived fatty acids have demonstrated tumor-suppressive activities, the anti-tumor effects of hexanoic acid, a characteristic component of milk fat, have not been thoroughly investigated. Model tumor mice orally administered hexanoate, the sodium salt of hexanoic acid, showed increased hexanoic acid concentrations in tumor-draining lymph nodes and tumor sites, with enhanced anti-tumor immune responses that significantly suppressed cancer cell growth. These effects were mediated through the following: (1) suppressed differentiation of naïve CD4+ T cells into Tregs; (2) decreased Treg-mediated inhibition of CD8+ T cells; and (3) suppressed intratumoral infiltration of Tregs, indirectly enhancing the effector function of CD8+ T cells. Furthermore, hexanoate enhanced the therapeutic effect of immune checkpoint inhibition therapy. Part of the protective effect of milk intake against CRC development may be mediated by hexanoic acid, which enhances anti-tumor immune responses through its actions on Tregs.