Lung cancer represents a significant clinical burden worldwide as the leading cause of cancer-related mortality, accounting for 19.4% of all cancer-related deaths. A key concept in lung cancer disease control is to prevent lung cancer progression in patients bearing premalignant lesions and to prevent lung cancer recurrence in those with previously treated lung cancer. Recent findings strongly support EGFR mutation testing in all patients with non-small cell lung cancer (NSCLC) and suggest that targeting EGFR for prevention will have significant impact in controlling this disease. The most common EGFR mutations (>90%) in lung cancer patients are deletions in exon 19 and/or point mutations in exon 21 (L858R). Mutations in KRAS, another major driver of lung cancer, are present in approximately 30% of lung cancer patients. KRAS mutations are also the major driver for several other human cancers including pancreatic and colon cancer, but efforts to target KRAS preventively or therapeutically have been unsuccessful. Since therapeutic efforts to inhibit RAS using small molecule inhibitors have been ineffective, peptide vaccination against tumor-specific mutant forms of RAS have received significant attention. Such immunological interventions are particularly important for high-risk individuals, for example former/current smokers and those with resected primary lung cancer at a high risk for relapse. Studies have shown that the Th1 helper cellular immunity is critical for immunotherapy-mediated cancer eradication. MHC II-restricted peptide vaccines elicit tumor antigen-specific Th1 immunity that orchestrates the reversal of immunesuppressive cytokine environment, recruitment of CD8+ Cytotoxic T lymphocytes (CTL), and escalation of the response via epitope spreading. Importantly, while MHC I–epitopes are highly HLA-DR restricted, MHC II epitopes can be designed to bind to multiple HLA-DR alleles and are thus applicable for broader populations of cancer patients. You et al designed MHC II-restricted multi-peptide vaccines against EGFR and KRAS, and showed that these vaccines can significantly (~80%) decrease oncoprotein-driven lung tumorigenesis in corresponding transgenic murine models of lung cancer when vaccinated before oncoprotein induction. However, diminished efficacy was observed when the vaccines were given two weeks after the oncoprotein induction, suggesting the presence of immunosuppressive mechanisms in the tumor microenvironment soon after the oncogene activation. High-risk individuals may already have active oncogenic mutations long before the onset of lung tumorigenesis, which could contribute significantly to an immune suppressive microenvironment, thereby hampering the vaccine-induced immune responses. Therefore, testing efficacy of a vaccine in combination with agents that can inhibit the immune suppressive microenvironment is highly significant. The Acetyl-CoA acetyltransferase (ACAT) inhibitor, Avasimibe (AVA), is an anti-inflammatory drug that has a good safety profile in clinical trials for treating atherosclerosis. Recent studies show that AVA promotes anti-tumor immune responses by increasing the effector function of tumor specific CD8+ cytotoxic T cells. Activated CD8+ T cells undergo alterations in cholesterol metabolism and synthesis to support rapid cell proliferation. AVA inhibits cholesterol esterification, upregulates plasma membrane cholesterol levels, enhances T-cell receptor (TCR) clustering, and promotes formation of the immunological synapse in CD8+ T cells. Recent work by You et al. demonstrated that the combination of AVA and their multipeptide KRAS vaccine could elicit improved anti-tumor efficacy both in a syngraft and transgenic mouse models of lung cancer, where KRAS activation was initiated long before vaccination. Based on these data, it is conceivable that chemo-immunoprevention strategies such as combination of AVA and cancer vaccines may be a rational approach to lung cancer prevention when the vaccine is administrated in the presence of subclinical disease. The combination is postulated to promote concurrent CD4+ and CD8+ T cell responses thereby providing an enhanced benefit to improve anti-tumor adaptive immune responses.