Intestinal estrogen receptor beta modulates the murine colon tumor immune microenvironment

Chronic inflammation contributes to the development of colorectal cancer, partly through its regulation of the microenvironment and antitumor immunity. Interestingly, women have a lower incidence of colorectal cancer, and estrogen treatment has been shown to reduce the occurrence of colorectal tumors. While intestinal estrogen receptor beta (ERβ, Esr2) can protect against colitis and colitis-induced cancer in mice, its role in shaping the tumor microenvironment remains unknown. In this study, we performed RNA sequencing to analyze the transcriptome of colonic epithelia and tumors from azoxymethane/dextran sulfate sodium-treated wild-type and intestinal ERβ knockout (ERβKO^Vil) mice and vehicle-treated controls. This revealed significant differences in gene expression and enriched biological processes influenced by sex and genotype, with immune-related responses being overrepresented. Deconvolution supported differential immune cell abundance and immunostaining showed that tumors from ERβKO^Vil mice displayed significantly increased macrophage infiltration, decreased T cell infiltration, and impaired natural killer cell infiltration. Further, ERβ mRNA levels in clinical colorectal tumors correlated with immune signaling profiles and better survival. Our findings indicate that intestinal ERβ promotes an antitumor microenvironment and could potentially affect the effectiveness of immunotherapy. These insights highlight the importance of ERβ in modulating antitumor immunity and underscore its therapeutic potential in colorectal cancer.