Kirsten rat sarcoma viral oncogene (K-ras) is a well-documented, frequently mutated gene in lung cancer. Since K-ras regulates numerous signaling pathways related to cell survival and proliferation, mutations in this gene are powerful drivers of tumorigenesis and confer prodigious survival advantages to developing tumors. These malignant cells dramatically alter their local tissue environment and in the process recruit a powerful ally: inflammation. Inflammation in the context of the tumor microenvironment can be described as either antitumor or protumor (i.e., aiding or restricting tumor progression, respectively). Many current treatments, like immune checkpoint blockade, seek to augment antitumor inflammation by alleviating inhibitory signaling in cytotoxic T cells; however, a burgeoning area of research is now focusing on ways to modulate and mitigate protumor inflammation. Here, we summarize the interplay of tumor-promoting inflammation and K-ras mutant lung cancer pathogenesis by exploring the cytokines, signaling pathways, and immune cells that mediate this process.

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K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis, and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. Absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced an NF-κB driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB driven immuno-suppressive response, and reduced anti-tumor cytotoxicity, while estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB driven immunosuppression, and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.