Overcoming EGFR-Mediated Dendritic Cell Dysfunction to Enhance Anti-tumor Immunity in EGFR-Mutant NSCLC by Precisely Targeting CD73 With pH-responsive Nanocarriers.

EGFR mutations remain a major challenge in immunotherapy for non-small cell lung cancer (NSCLC), with poor responses to immune checkpoint inhibitors driven by mechanisms associated with EGFR mutation-mediated tumor microenvironment (TME) modulation. This study reveals that EGFR mutations prominently impaired dendritic cell (DC) maturation, disrupting their capacity to effectively prime CD8+ T cells and thereby compromising anti-tumor immune responses. By application of clinical specimen analyses, multi-omics approaches, and in vivo mouse models, this work demonstrates that EGFR mutations elicited adenosine production through the ERK/c-Jun signaling axis in tumor cells, establishing an immunosuppressive TME that impeded maturation and antigen presentation of DCs, and in turn weakened CD8+ T cell activation. To overcome the EGFR mutation-induced immunosuppression, this work next develops F127ZIF-8AB680, a pH-responsive and tumor-selective nanodrug specifically designed to target the CD73-adenosine pathway within the acidic TME. This nanodrug significantly improves the therapeutic efficacy of PD-1 blockade, leading to robust tumor growth inhibition and prolonged survival of mice in EGFR-mutant NSCLC models. Leveraging the advanced nanotechnology, this newly designed pH-sensitive nanocarrier introduces a precise CD73/adenosine inhibition within the acidic TME that reprograms the immune landscape in EGFR-mutant NSCLC, which represents a promising therapeutic strategy to overcome immunotherapy resistance in NSCLC.