Abstract

KRAS–LKB1 (KL) co-mutant non-small cell lung cancer (NSCLC) is characterized by an immunologically “cold” tumor immune microenvironment (TIME), and resultantly exhibits intrinsic resistance to immune checkpoint inhibitor (ICI) therapy. Developing effective strategies to remodel the TIME and overcome ICI resistance remains an urgent clinical need. Single-cell RNA sequencing (scRNA-seq) identified PGAM5 as a therapeutic target in patients with KL co-mutant NSCLC. Functional inhibition of PGAM5 suppressed mitochondrial autophagy and promoted necroptosis, thus activating the cGAS–STING pathway in synergy with the DNA methyltransferase inhibitor decitabine (DAC). Guided by these findings, we engineered a lipid nanoparticle (LNP) modified with arginine-glycine-aspartic acid (RGD) peptides (LNP-RGD) to target integrin αvβ3 on tumor cells, enabling co-delivery of mouse Pgam5 siRNA (siPgam5) and DAC (LNP-RGD-DAC). In the Kras LSL−G12D/+ Lkb1 fl/fl (KrasLkb1) genetically engineered mouse model (GEMM), LNP-RGD-DAC achieved efficient intratumoral delivery, robustly inducing necroptosis of the cancer cells and cGAS–STING activation. Notably, such a combinational therapy featuring LNP-RGD-DAC and programmed death-1 (PD-1) blockade has resulted in almost complete tumor regression, accompanied by a progressive increase in tumor infiltration of CD8 + T cells, CD11c + dendritic cells (DCs), and NK1.1 + natural killer (NK) cells, as well as their activated subsets. This rationally designed lipid nanoparticle system not only enables precise tumor targeting but also achieves efficient and selective co-delivery of nucleic acid and small-molecule drugs, offering a highly translationally promising nanotherapeutic platform to overcome immunotherapy resistance in refractory KL co-mutant NSCLC.