Although photothermal therapy (PTT) has become a compelling strategy for cancer therapy, few studies concern the physiological consequences of PTT ablation. Herein, we discover that PTT-induced hyperthermia can aggravate tumor hypoxia, which may increase the risk of tumor recurrence and reduce PTT efficacy. We thus integrated the pH/hypoxia-triggered Fe(iii)-banoxantrone (AQ4N) prodrug and semiconducting polymer dots (SPs) for programmable triggered cancer photothermal-chemotherapy. A SP-hybridized mesoporous silica framework, decorated by dopamine and polyethylene glycol, named PPMSF, was synthesized by a simple method, and then served as an efficient photo-absorbing agent (PTA) and drug carrier. Fe(iii)-AQ4N and Mn(ii) were then coordinated with PPMSF (abbreviated Mn-APPMSF) via coordination effects. The nanohybrids exhibited tumor micro-environment pH triggered drug release. Under the irradiation of NIR light, magnetic resonance imaging (MRI) tracked the accumulation of the nanohybrids in tumors which then destroyed tumor cells by local hyperthermia, this can consequently aggravate the tumor hypoxia levels. Intriguingly, the aggravated hypoxia can further enhance the reduction of AQ4N to significantly improve therapeutic efficacy and effectively inhibit tumor growth when compared with traditional PTT. These results indicate the potential of our nanohybrids as a programmable synergistic agent for cancer therapy.