Enhancing the Therapeutic Efficacy of PD-1 Blockade by Targeting LAMP2A to Inhibit Lysosomal Degradation of STING and TBK1

Abstract

LAMP2A stands as a pivotal translocase enzyme in the process of companion-mediated autophagy (CMA). The STING/TBK1 axis assumes paramount significance in antitumor immunity. The objective of this investigation is to delve into the mechanistic intricacies of CMA degradation orchestrated by STING/TBK1, and to discern whether targeting LAMP2A can potentiate the efficacy of PD-1 blockade. Herein, through in vitro and in vivo experimentation, coupled with scrutiny of clinical specimens, we have ascertained that STING/TBK1 has emerged as a novel substrate within the ambit of CMA, and that LAMP2A serves as a critical regulator of STING/TBK1. Simultaneously, the silencing of LAMP2A exerts an inhibitory influence upon the malignant comportment of HNSCC cells in a STING and TBK1-dependent fashion. Finally, we validate that the targeting of LAMP2A augments the recruitment of GZMB+/GZMB+PD-1+CD8+T cells, thereby ameliorating the frigid tumor milieu. Grounded in these mechanisms, the combinatorial employment of a LAMP2A inhibitor, specifically Diclofenac, in conjunction with PD-1 blockade, conspicuously incites the activation of infiltrating CD8+ T cells, thereby suppressing tumor growth. Consequently, our research unveils a prospective co-therapeutic strategy, harnessing Diclofenac (a LAMP2A inhibitor) alongside PD-1 blockade to enhance antitumor efficacy.

Note:

Funding Information: This work was supported by the Natural Science Foundation of China (NSFC 82173638), Natural Science Foundation of Heilongjiang Province, China (07000044), the Independent Exploration and Innovation Program of Central South University (2023ZZTS-0584).

Conflict of Interests: The authors declare no competing interests.

Ethical Approval: This study was approved by the Ethics Committee of Harbin Medical University Cancer Hospital, China. All patients provided written informed consent to participate in this research. The research methodology adhered to the standards outlined in the Helsinki Declaration.

Keywords: Chaperone-mediated autophagy, LAMP2A, STING, TBK1, HNSCC, PD-1