Restoring antitumor immunity and improving immunotherapy outcomes in KRAS-mutant NSCLC through MYC inhibition by OMO-103

Background: MYC is a key oncogenic driver that promotes tumor progression, immune evasion, and therapy resistance. In KRAS-mutant non-small-cell lung cancer (NSCLC), where effective treatments remain limited, MYC functions as a major downstream effector of RAS signaling. High MYC expression in KRAS-mutant NSCLC patient samples is associated with reduced immune engagement and suppression of Tumor Necrosis Factor (TNF) superfamily pathway, suggesting a role for MYC in shaping the tumor immune microenvironment (TIME). We investigated whether MYC inhibition using OMO-103 (Omomyc), the first clinically viable direct MYC inhibitor, could reprogram the TIME and enhance immunotherapy response. Methods: We performed transcriptomic analysis of KRAS-mutant NSCLC patient samples and generated a KRAS G12D -driven transgenic mouse model exhibiting MYC-dependent immunosuppression. Using cell lines derived from this model, we evaluated the effects of MYC inhibition on proliferation and immune-related signaling. In vivo studies were conducted in multiple KRAS-driven NSCLC mouse models to assess tumor growth, immune infiltration, and TNF receptor pathway activation. Clinical relevance was examined through analysis of patient samples from the MYCure Phase I trial (NCT04808362). Results: MYC inhibition impaired cell proliferation and upregulated multiple immune-activating pathways in vitro . In vivo , OMO-103 halted tumor progression, increased immune cell infiltration, and enhanced activation of TNF receptor family members-including OX-40 and 4-1BB-on tumor-infiltrating T cells, driving secretion of interferon-gamma and TNF-alpha. Combining OMO-103 with TNFR-targeting immunotherapies resulted in significantly greater tumor regression and overall response rate than monotherapy. Analysis of MYCure patient samples confirmed that OMO-103 induces a more immune-active TIME, with increased interferon response and antigen presentation. Notably, patients with clinical benefit displayed increased expression of TNF superfamily members in tumors and serum, with the KRAS-mutant NSCLC patient showing the highest induction. Conclusions: MYC inhibition with OMO-103 not only suppresses tumor growth but also reprograms the TIME to promote anti-tumor immunity and enhance response to immunotherapy. These findings support MYC blockade as a promising therapeutic strategy to overcome immunotherapy resistance in KRAS-mutant NSCLC.