Current cancer treatment is not only limited to monotherapy but is also influenced by limited drug delivery options. Combined chemokinetic-photokinetic therapy has great promise in enhancing anticancer effects. Meanwhile, zein has superior self-assembly properties and can be loaded with photosensitizers. Herein, the targeted multifunctional nanoparticles based on zein/hyaluronate acid (HA)/tannin (TA)/Cu2+ loaded with IR780 (ZHTC@IR780) are constructed for synergetic cancer therapy by chemo-dynamic therapy (CDT) and photodynamic therapy (PDT). There is experimental proof that ZHTC@IR780 nanoparticles (NPs) can relieve the tumor hypoxic microenvironment by catalytic decomposition of endogenous H2O2 to O2 and further react with O2 to produce toxic 1O2 with 808 nm laser irradiation. The glutathione oxidase-like effects of ZHTC@IR780 NPs can generate Fenton-like Cu+ ions and deplete GSH for efficient hydroxyl radical (•OH) production. In addition, CDT combined with PDT enhances the antitumor effect. Photodynamic therapy can cause immunogenic cell death, increase calreticulin eversion, release histone with high mobility, and promote apoptosis of tumor cells.