Indocyanine green-/TLR7 agonist-constructed thermosensitive liposome for low-temperature PTT induced synergistic immunotherapy of colorectal cancer

Colorectal cancer (CRC) is a lethal malignancy with a high mortality rate due to its low immunogenic-ity, the strong immunosuppressive milieu and poor drug permeability. To overcome these obstacles, a cascade synergistic nanosystem (denoted as R837/ICG@Lip) was developed via self-assembly of heater indocyanine green (ICG) and toll-like receptor-7 agonist imiquimod (R837) into thermosensitive lipo-some for simultaneous induction of immunogenic cell death (ICD) and reversing of suppressive tumor microenvironment. The obtained nanoparticles exhibited NIR-triggered drug release, good photothermal conversion efficiency and phototoxicity towards CT26 colorectal cancer cells. In vivo results reveal that the R837/ICG@Lip could be effectively accumulated in CT26 subcutaneous tumors and the draining lymph nodes. More importantly, R837/ICG@Lip-mediated low-temperature photothermal therapy triggers ICD, promotes the maturation of host dendritic cells (DCs), and subsequently amplifies adaptive antitumor T-cell responses, resulting in 'Cold to Hot' transition. Besides directly affecting immune cells, the secretion of some immune-related cytokines further indirectly boosted anti-cancer immunity. After combining with the indoleamine 2,3-dioxygenase (IDO) inhibitor, the systemic antitumor immune response was further augmented, achieving best tumor inhibition effects. Thus, low-tem perature mediated photoimmunother-apy targeting multiple antitumor immune pathways boost synergistic antitumor immunity of tolerance tumors.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

A cascade synergistic nanosystem, R837/ICG@Lip, was developed to overcome the obstacles of low immunogenicity, immunosuppressive tumor microenvironment, and poor drug permeability in colorectal cancer (CRC). The nanosystem demonstrated NIR-triggered drug release, photothermal conversion efficiency, and phototoxicity against CT26 colorectal cancer cells. In vivo results showed effective accumulation of the nanosystem in tumors and lymph nodes, triggering immunogenic cell death and promoting adaptive antitumor T-cell responses. Combining with an IDO inhibitor further enhanced the antitumor immune response.