Suppression of STK11 induces expansion of polymorphonuclear myeloid-derived suppressive cells and activation of immune signaling in breast cancer

The tumor microenvironment in breast cancer is typically immunosuppressive. Combined neoadjuvant chemotherapy and immunotherapy is the standard of care for high-risk, triple-negative breast cancer patients, but it is not routinely applied to other breast cancer subtypes. Somatic mutation of STK11 (serine/threonine kinase 11), a tumor suppressor, occurs in the MSK-IMPACT platform in 1.9% of 3116 breast cases. A potential link between inactivation of STK11 and immune response regulation has been suggested in breast cancer, but the impact of STK11 suppression on tumor–immune interactions remains under investigation. In this study, we established Stk11-knockout (Stk11-KO) mouse breast cancer cell lines, performed RNA sequencing and cytokine array analysis to assess alterations in gene expression and cytokine profiles. Our results revealed significant enrichment of several immune-related pathways and a marked increase in C-X-C motif chemokine ligand 1 (Cxcl1) expression in response to Stk11 knockout. Moreover, analysis of breast cancer patient samples showed an inverse association between the plasma CXCL1 levels and STK11 expression. To evaluate the in vivo effects of STK11 loss, we established an orthotopic breast cancer model in immunocompetent female mice. Tumors derived from Stk11-KO mouse breast cancer cells demonstrated greater tumorigenicity. In addition, mice-bearing Stk11-KO tumors exhibited elevated levels of circulating polymorphonuclear myeloid-derived suppressive cells. In summary, STK11 suppression enhances immune-related pathways and promotes Cxcl1 expression, correlating with the expansion of immunosuppressive MDSC populations. Our findings suggest that targeting STK11-associated immunosuppressive mechanisms may provide a novel therapeutic option for STK11-deficient breast cancer patients.