Photodynamic therapy (PDT) has been a well-accepted clinical treatment for malignant tumors owing to its noninvasiveness and high spatiotemporal selectivity. However, the efficiency of PDT is still severely hindered by an inherent aggregation-caused quenching (ACQ) effect of traditional photosensitizers (PSs), the presence of B-cell lymphoma 2 (Bcl-2), an antiapoptosis protein in cells, and hypoxia in the tumor microenvironment. To address these issues, hybrid nanospheres containing Fe, aggregation-induced emission (AIE) PS, and Bcl-2 inhibitor of sabutoclax were constructed coordination-driven self-assembly in aqueous media. Once the hybrid nanospheres are taken up by tumor cells, intracellular O concentration is observed to increase Fenton reaction driven by Fe, whereas intracellular PDT resistance of the AIE PS was mitigated by sabutoclax. The design of the multifunctional hybrid nanospheres demonstrates a prospective nanoplatform for image-guided enhanced PDT of tumors.