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

The advance of immunotherapy has shifted the paradigm of cancer management in clinics. Nevertheless, a considerable subset of pancreatic ductal adenocarcinoma (PDAC) patients marginally respond to current immunotherapy due to the occurrence of dynamic immune evasion arising from intrinsic and therapeutic stress. In this investigation, the pivotal role of pancreatic cancer-associated fibroblast (CAF)-induced fibrosis and tumor cell-mediated T-cell exhaustion in driving the dynamic immune evasion is identified. Building upon this discovery, the authors herein engineer a novel peptide-drug conjugate (PDC)-based self-adaptive nanoregulator for mitigating dynamic immune evasion of PDAC. The resulting nanoregulator can perform a two-stage morphology transformation from spherical micelle to nanofiber, and subsequently from nanofiber to spherical nanoparticles. Such kind of nanostructure design can 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 may provide a novel avenue for enhanced PDAC immunotherapy. A peptide-drug conjugate (PDC)-based self-adaptive nanoregulator with first-stage spherical micelle to nanofiber, and second-stage nanofiber to spherical nanoparticles morphology transformation performance, is developed for tailoring dynamic immune evasion of PDAC. The nanoregulator is demonstrated to intervene in cancer-associated fibroblast-mediated tumor fibrosis and reverse 2,3-dioxygenase 1-kynurenine axis-involed T-cell exhaustion.image

Automated summary

The weak response of pancreatic cancer patients to immunotherapy is attributed to cancer-associated fibroblast-induced fibrosis and tumor cell-mediated T-cell exhaustion. A self-adaptive nanoregulator has been developed to intervene in tumor fibrosis and reverse T-cell exhaustion, providing a novel approach to enhance PDAC immunotherapy.