Integration of multiple functions into one simple nanocomposite is of high significance for achieving an effective tumor-killing effect. Herein, an effective synergistic strategy is designed and developed for tumor cell killing, which integrates Fenton-induced chemodynamic therapy (CDT) and near-infrared (NIR) laser-mediated photothermal therapy (PTT)/photodynamic therapy (PDT). This nanocomposite is composed of an iron (Fe) ions-decorated polypyrrole (PPy) core, IR820 payload, and bovine serum albumin (BSA) coating. PPy nanoparticles were prepared through a facile polymerization method using Fe(III) as the oxidation agents, followed by BSA coating and IR820 loading to finally obtain PPy(Fe)-IR820-BSA. The decorated iron ions can catalyze H2O2 into •OH through Fenton reaction to kill tumor cells. The energy of the irradiated NIR light is converted into heat by PPy and IR820, inducing hyperthermia-mediated cell damage. Meanwhile, toxic 1O2 is produced by IR820 under laser irradiation, performing PDT against tumor cells. Cell study data display that significant tumor cell killing effect can be achieved by PPy(Fe)-IR820-BSA under laser irradiation, demonstrating the superiority of synergistic PTT/PDT/CDT. The expression of calreticulin is up-regulated and consequently activates immunogenic cell death, promising in thorough tumor elimination. [ABSTRACT FROM AUTHOR]