Four Birds with One Stone: A Multifunctional Polypeptide Nanocomposite to Unify Ferroptosis, Nitric Oxide, and Photothermia for Amplifying Antitumor Immunity

Abstract Tumor metastasis and relapse mainly results in therapy failure and becomes a big challenge in oncology. Immunogenic cell death (ICD) of tumors mediated immunotherapy (IT) is attracting widely for solving that problem although achieving sufficient ICD and strong immune response is challenging for nanoparticles‐based cancer IT. Herein, a multifunctional polypeptide coordinate nanocomposite that possesses near infrared photothermia (PT) and responsive releases of nitric oxide (NO) and iron ions is constructed, which synergistically kills cancer cells and highly prohibits metastatic 4T1 cells invasion and migration by PT‐boosted NO release and ferroptosis (FT). Remarkably, triple FT‐NO‐PT treatment amplifies the ICD effects and outperforms combo/monotherapy FT‐PT and FT in cancer cells and tumors, which further activates dendritic cells maturation, and primed CD4⁺T and CD8⁺T cells immune responses and memory effects, playing four birds with one stone (i.e., FT‐NO‐PT‐IT). The PCSFG‐based FT‐NO‐PT not only fully eradicates 4T1 primary tumors, but also induces strong ICD, immune priming, and memory effects to reject rechallenged 4T1 tumors and inhibit malignant tumor metastasis, demonstrating synergistic amplified ICD effects with strong cell immunities and memory effects by a unified FT‐NO‐PT‐IT.