Tumor and intratumoral pathogen cascade-targeting photothermal nanotherapeutics for boosted immunotherapy of colorectal cancer.

Clinical benefits of immunotherapy in colorectal cancer (CRC) are limited due to the low immunogenicity and immunosuppressive tumor microenvironment. Fusobacterium nucleatum (Fn) is discovered to colonize CRC tumors and dampen immunotherapy by fostering an immunosuppressive TME. Herein, a controllable "Shielding-deshielding" N-acetylgalactosamine (GalNAc)-derived photothermal nanotherapeutic is developed to mediate cascade targeting toward tumor and intratumoral Fn for enhanced photothermal-immunotherapy. This nanotherapeutic can in situ generate near infrared-II laser-activatable photothermal agent by reacting with endogenous hydrogen sulfide in CRC. The Schiff bond-tethered hyaluronic acid coating not only facilitates precise localization within CRC but shieldes GalNAc-mediated liver targeting, which can be deshielded upon a slightly acidic TME to anchor Fn by binding to its lectin Fap2. This cascade-targeting nanotherapeutic enables efficacious tumor accumulation and reinforces photothermal therapy (PTT) efficacy. Notably, PTT efficiently induces immunogenic cell death in CRC cells, leading to augmented immunogenicity and CD8 T cell activation. Meanwhile, synchronous eradication of Fn facilitates M1 macrophage polarization, and promotes intratumoral infiltration of CD8 T cell by reducing succinic acid level, thereby further boosting antitumor immunity against both primary and distant tumors. Overall, this study involving cascade targeting-reinforced PTT and intratumoral microorganism modulation offers new insight into effective CRC immunotherapy.