Mild hyperthermia promotes immune checkpoint blockade-based immunotherapy against metastatic pancreatic cancer using size-adjustable nanoparticles

Immune checkpoint blockade treatment is one of the most promising immunotherapies, which exhibits promising therapeutic effects on inhibition of metastasis. However, immunotherapy has little effect on pancreatic cancer, due to its extensive fibrotic matrix and immunosuppressive tumor microenvironment. Mild hyperthermia induced by photothermal therapy (PTT) has been proven to activate the immune responses in the tumor microenvironment. Herein, we designed a combine strategy of mild hyperthermia and immune checkpoint blockade (BMS-202) treatment with size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL), in which BMS-202 loaded small-sized albumin nanoparticle (HSA-BMS) was encapsulated. Mild hyperthermia reduced the tumor hypoxia, relieved the interstitial pressure and increased the recruitment of endogenous immune cells in tumors. In the meantime, small-sized HSA-BMS was released from large-sized HSA-BMS@CAP-ILTSL in response to fibroblast activation protein-α (FAP-α) and near-infrared (NIR) laser, and enhanced the immunological responses by recovering the activity of T lymphocytes, accompanied by secreting relevant cytokines (TNF-α and IFN-γ). The combined therapy (HSA-BMS@CAP-ILTSL) could not only significantly suppress the tumor growth in vivo, but also decrease the amounts of metastatic nodules in distant organs. These results suggested that size-adjustable nanoparticles had a great potential in the treatment of metastatic pancreatic cancer. STATEMENT OF SIGNIFICANCE: The desmoplastic stroma and hypoperfusion of pancreatic cancer imposed physical barriers to effective therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We constructed size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL) with size around 120 nm, where small sized albumin nanoparticle (10 nm) of immune checkpoint inhibitor (HSA-BMS) were encapsulated inside. Mild hyperthermia not only contributed to release HSA-BMS for penetration (blocking the immunosuppressive signals deep in the tumor), but enhanced tumor blood perfusion for infiltration of endogenous immune cells. In the two-pronged treatment, the pancreatic cancer immunotherapy significantly enhanced and the risk of cancer metastasis was reduced. Overall, the strategy provides a promising approach to increase drug accumulation and improve the anti-tumor immune activity in pancreatic cancer.