Enhanced therapeutic efficacy of anti-PD-1 blockade by targeting LAMP2A inhibits lysosomal degradation of STING and TBK1

<b>Rationale:</b> LAMP2A is a key translocase in chaperone-mediated autophagy (CMA), and the STING/TBK1 axis is crucial in antitumor immunity. This study explored the complex mechanisms by which CMA regulates the STING/TBK1 degradation and whether targeting LAMP2A could enhance the efficacy of PD-1 monoclonal antibodies. <b>Methods:</b> The expression of STING and TBK1 was detected after treatment with various inhibitors of protein degradation pathways. Confocal microscopy was used to detect the localization of STING and TBK1 in lysosomes. R software was used to analyze LAMP2A expression and prognosis. The biological function of LAMP2A was examined by <i>in vitro</i> and <i>in vivo</i> experiments. <b>Results:</b> Through <i>in vitro</i> and <i>in vivo</i> experiments and a review of clinical specimens, we identified STING/TBK1 as a novel substrate of CMA. Downregulation of LAMP2A enhanced IFNβ production and cellular antiviral response by inhibiting CMA-mediated degradation of STING and TBK1. Based on these observations, further <i>in vivo</i> experiments confirmed that the LAMP2A loss combined with PD-1 monoclonal antibodies significantly stimulated the activation of infiltrating CD8+ T cells, thereby inhibiting tumor growth. Also, non-responder head and neck squamous cell carcinoma (HNSCC) patients undergoing neoadjuvant immuno-chemotherapy had higher levels of LAMP2A and lower levels of PD-L1 expression in their tumor tissues. <b>Conclusions:</b> Our study has revealed a prospective combination therapy, in which diclofenac functioning as a LAMP2A inhibitor, enhances the anti-tumor efficacy of PD-1 monoclonal antibody by inhibiting the degradation of STING and TBK1.