Rationally designed anti-autophagy nanosystems for reversing the immunosuppressive network in the tumor environment.

Abstract

Aims: To develop a nano-immunotherapy system combining autophagy inhibition and innate immune activation to reverse the immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC).

Materials & methods: The pH-responsive polymer PC7A was utilized to co-deliver the autophagy inhibitor chloroquine (CQ) and the STING agonist cyclic diguanylate (CDG), forming the CQCP nanosystem. In vitro and in vivo experiments evaluated autophagy inhibition, MHC-I expression, dendritic cell activation, tumor infiltration of lymphocytes, and survival in PDAC-bearing mice.

Results: CQCP enhanced MHC-I expression on PDAC cells by 2.1-fold (p < 0.001) and increased activated dendritic cells (CD86+/CD40+) by 3.5-fold (p < 0.01) in the TME. Tumor-infiltrating CD8+ T cells rose by 42.6% (p < 0.001), and systemic immune activation in peripheral lymphoid tissues was observed. CQCP achieved an 86% survival rate in tumor-bearing mice, significantly outperforming monotherapies or free drug combinations.

Conclusions: The CQCP system synergistically reverses PDAC immunosuppression by restoring antigen presentation and activating innate immunity. This dual-targeted strategy demonstrates robust antitumor efficacy and offers a promising immunotherapy approach for PDAC.