The inflammatory response is one of the general symptoms that accompany tumorigenesis, and the pro-inflammatory factors cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandin-2 (PGE-2) in the inflammatory environment surrounding tumors possess promoting effects during tumor development，metastasis and angiogenesis. In addition, the hypoxic environment of tumors severely limits the effectiveness of photodynamic therapy (PDT). By using a spatiotemporal controlled Gelatin coated polydopamine (PDA@GN) as the carrier, and loaded with the chemotherapeutic drug doxorubicin (DOX), the photosensitizer indocyanine green (ICG), the PDT enhancer MnO2 and the anti-inflammatory drug celecoxib (CEL) individually, we developed an effective and universal extracellular-intracellular "on-demand" release nanomedicine DOX@PDA-ICG@MnO2@GN-CEL for the combined fight against malignant tumors. Our results showed that GN could release CEL extracellularly by MMP-2 response at tumor microenvironment (TME) and inhibit the COX-2/PGE-2 pathway, which could reduce chemotherapy resistance, attenuate the concurrent inflammation and the damage to surrounding normal cells of photothermal therapy (PTT) induced by PDA and ICG. After entering the tumor cells, PDA released DOX, ICG and MnO2 intracellularly through acid response. MnO2 promoted the degradation of endogenous H2O2 to generate oxygen under acidic conditions to alleviate the tumor hypoxic environment, which enhanced PDT triggered by ICG, PDA and ICG exhibited PTT synergistically, and DOX exerted chemotherapy with little chemotherapy resistance. The dual response drug release switch enabled the chemotherapeutic, photothermal, photodynamic and anti-inflammatory drugs precisely acted on different sites of tumor tissues and realized a promising multimodal combination therapy.