Macrophage Antigen Presentation Is Unleashed by Pan-RAS Inhibition to Promote Antitumor Immunity

Pan-RAS inhibitors have emerged as potent targeted therapies designed to suppress oncogenic signaling in RAS-mutant tumors. However, whether these inhibitors possess therapeutic utility beyond tumors with intrinsic RAS dependency remains unclear. Here we show that the clinical-stage pan-RAS(ON) inhibitor RMC-6236 (Daraxonrasib) induces robust regression of NRAS-wild-type B16 tumors in immunocompetent mice, a response mediated by a mechanism independent of direct tumor-cell targeting. Instead, RMC-6236 acts by remodeling the tumor microenvironment, specifically enhancing the antigen-presenting capacity of tumor-associated macrophages through upregulated MHC-I expression. This anti-tumor efficacy is abrogated in T cell-deficient hosts, identifying a macrophage-dependent, T cell-mediated mechanism of control. Mechanistically, RMC-6236 does not directly block canonical RAS signaling in macrophages. Rather, it suppresses a Myc-Hdac2 epigenetic program, leading to enhanced histone H4 acetylation at the Nlrc5 locus and subsequent activation of the MHC-I master regulator NLRC5. Together, our findings reveal a macrophage-centered, epigenetically wired immune mechanism for pan-RAS inhibition that broadens the therapeutic scope of targeting the "undruggable" RAS pathway beyond tumor genotype towards systemic immune modulation.