Mannosylated Fluoropolypeptide Nanovaccines Remodeling Tumor Immunosuppressive Microenvironment to Achieve Highly Potent Cancer Immunotherapy

Abstract It is challenging for nanovaccines (NVs) to effectively deliver antigens/neoantigens to prime specifically potent immunities and remodel immunosuppressive tumor microenvironment (TME) for combating immune “cold” cancers. Herein, a novel kind of mannosylated fluoropolypeptide NVs of MFPCOFG (i.e., mannosylated fluoropoly( D,L ‐cysteine) ovalbumin‐loaded Fe 2+ ‐gallic acid) is designed that synergistically integrates triple antigen‐metal‐thermoimmunity to remodel immunosuppressive TME and achieve highly potent immunities. MFPCOFG plus near‐infrared irradiation (NIR) effectively facilitated antigen uptake and escape, induced the maturation and antigen cross‐presentations of dendritic cells and macrophages, polarized anti‐inflammatory macrophage phenotype M2 into tumoricial M1, primed potent CD4 + /CD8 + T cells responses, proinflammatory cytokines secretion and immune memory effects, showcasing triple antigen‐metal‐thermoimmunity outperforming combo/mono‐immunity. Importantly, both MFPCOFG + NIR and personalized NVs can remarkably enhance the tumor infiltration of CD4 + /CD8 + T and NK cells to boost potent immunities and long‐lasting memory effects, reduce regulatory T (Tregs) and M2 to remodel immunosuppressive TME in B16‐OVA and 4T1 models, achieving superior tumor prevention, ablation, and tumor relapse and metastasis inhibition, as further orchestrated with anti‐PD‐1. Consequently, this work opens up a new avenue to design biocompatible polypeptide nanovaccines with potent immune‐priming and TME‐remodeling capabilities, holding great potentials to combat immune “cold” cancers with clinic‐used anti‐PD‐1 for cancer immunotherapy and personalized immunotherapy.