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

Abstract 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 F127 ZIF‐8 AB680 , 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.