Self-Adaptive Nanoregulator to Mitigate Dynamic Immune Evasion of Pancreatic Cancer.

The advance of immunotherapy has shifted the paradigm of cancer management in clinic. Nevertheless, a considerable subset of pancreatic ductal adenocarcinoma (PDAC) patients marginally responds to current immunotherapy due to the occurrence of dynamic immune evasion arising from the intrinsic and therapeutic stress. In this investigation, we identified the pivotal role of pancreatic cancer-associated fibroblast (CAF)-induced fibrosis and tumor cell-mediated T-cell exhaustion in driving the dynamic immune evasion. Building upon this discovery, we herein engineered a novel peptide-drug conjugate (PDC)-based self-adaptive nanoregulator for mitigating dynamic immune evasion of PDAC. The resulting nanoregulator could perform two-stage morphology transformation from spherical micelle to nanofiber, and subsequently from nanofiber to spherical nanoparticles. Such kind nanostructure design could facilitate differentialized delivery of CAF inhibitor in the extracellular matrix for intervening CAF-mediated tumor fibrosis, and indoleamine 2,3-dioxygenase 1 inhibitor to tumor cells for relieving IDO1-kynurenine axis-induced T-cell exhaustion. Antitumor study with the self-adaptive nanoregulator elicited persistent antitumor immunity and remarkable antitumor performance in both Panc02 and KPC tumor models in vivo. Taken together, the PDC-based self-adaptive nanoregulator might provide a novel avenue for enhanced PDAC immunotherapy. This article is protected by copyright. All rights reserved.