Micellar co-delivery of KRAS-mutant inhibitors and TLR7/8 agonists synergizes targeted therapy and immunotherapy in lung cancer.

Abstract

KRAS-mutant lung cancers pose significant clinical challenges. Despite promising advance in covalent KRAS G12C inhibitors, many patients with G12C mutation reveal limited responses, due to rapid emergence of resistance and heterogeneous nature of KRAS mutations. Here, we report a reduction-sensitive micellar system for the codelivery of a KRAS G12C inhibitor (adagrasib, KI) and a TLR7/8 agonist (R848, TA) (mKITA), aiming to synchronize direct oncogenic signaling blockade with potent immune modulation within tumor microenvironment (TME). In KRAS G12C-mutant lung cancer LLC cells, mKITA displayed enhanced autophagy and apoptosis, inducing marked immunogenic cell death at an optimal KI/TA molar ratio of 8/1. This in turn, stimulated dendritic cell (DC) maturation, proinflammatory cytokine secretion, and robust T cell activation-manifesting as a pronounced in situ vaccine effect. In an orthotopic LLC model, systemic administration of mKITA brought about significant survival benefits, and remodeled the suppressive TME by depleting immunosuppressive MDSCs, Tregs and M2M, and recruiting effector immune subsets (DCs, IFN-γ⁺CTLs, Th1). Notably, combination therapy with αPD-1 achieved 60% complete tumor eradication and long-term survival, accompanied by epitope spreading and humoral responses against both KRAS and WT1 antigens. These results suggest that mKITA is capable of enabling in situ vaccination and overcoming key barriers in KRAS-driven lung cancer. This strategy appears as a potential generalizable approach to orchestrate durable, multilayered antitumor immunity and address the clinical challenge of resistance and immunosuppression in KRAS-mutant lung cancers. STATEMENT OF SIGNIFICANCE: KRAS-mutant lung cancer represents a major clinical challenge due to its resistance to both targeted kinase inhibition and immunotherapy. Current strategies provide limited efficacy because of tumor heterogeneity, rapid adaptation, and the immunosuppressive TME. We develop a reduction-sensitive micellar nanoplatform (mKITA) that enables synchronized, spatiotemporally controlled co-delivery of a KRAS G12C inhibitor and a TLR7/8 agonist. mKITA induces autophagy- and apoptosis-associated ICD, and primes APCs to trigger robust in situ T cell activation. This strategy effectively remodels immunosuppressive TME by depleting MDSCs while recruiting CTLs and Th1 cells. In orthotopic lung cancer models, combining mKITA with αPD-1 achieves complete tumor regression and long-term survival in 60% of mice. This strategy offers a clinically translatable nanomedicine to overcome resistance in KRAS-driven lung cancer.