Inducing immunogenic cell death (ICD) by external-stimuli therapy holds great promise for cancer immunotherapy, however, hindered by widely-used photodynamic therapy (PDT) and sonodynamic therapy (SDT) due to oxygen depletion that compromises their therapeutic effect. Herein, we report a natural sericin nanoparticle (denoted as SDINPs) as ICD-inducer based on photothermal therapy (PTT) to alleviate immunosuppressive tumor microenvironment. The sericin-based ICD-inducer comprises chemically conjugated pH-responsive chemotherapeutic drugs, doxorubicin (DOX), and a physically loaded photosensitizers, indocyanine green (ICG), the therapeutic ability of which can be specifically activated by non-invasive laser radiation. Compared to free molecules, nanostructured SDINPs exhibit superior photothermal conversion efficiency, prolonged blood circulation time, and enhanced tumor accumulation, retention, and penetration capabilities. As a result of these advantages, they demonstrate potent therapeutic efficacy and PTT-mediated ICD burst induction for antitumor immunity. This study presents a pH/photo-activatable combination strategy that provides a novel perspective for clinical cancer treatment.