Integrin-Targeted, Activatable Nanophototherapeutics for Immune Modulation: Enhancing Photoimmunotherapy Efficacy in Prostate Cancer Through Macrophage Reprogramming

Prostate cancer is an epithelial malignancy with a high incidence among elderly men. Photochemistry-based dye photodrugs (known as photosensitizers) offer a promising clinical approach for treating tumors. These agents work by inducing immunogenic cell death (ICD), which activates antitumor immune response. This approach is favored owing to its minimal invasiveness, low toxicity, and high efficiency. However, the immunosuppressive microenvironment of characteristics of “cold” tumors significantly restricts the clinical efficacy of photodrugs. Developing an advanced nanocarrier system to deliver photodrugs and immune agonists for efficient drug delivery to tumor lesion sites and to reshape the immunosuppressive microenvironment is crucial in clinical practice. Therefore, in this study, we designed an integrin-targeted, activatable nano photodrug co-assembly with an immune agonist (RPST@IMQ) for enhancing photoimmunotherapy in prostate cancer via the reprogramming of tumor-associated macrophages. The active-targeted nanosystem enhanced the dosage of photodrug at the lesion site through systemic administration. High doses of glutathione at the tumor site cleaved the disulfide bonds of RPST@IMQ, releasing the photodrug and the immune agonist imiquimod (IMQ). Under photoirradiation, the photodrug generated significant doses of singlet oxygen to eliminate tumor cells, thereby inducing ICD to activate antitumor immune responses. Simultaneously, the released IMQ reprograms immunosuppressive M2-type tumor-associated macrophages (TAMs) in the tumor microenvironment into M1-type TAMs with tumor-killing capabilities, thereby converting “cold” tumors into “hot” tumors. This conversion enhances the therapeutic efficacy against primary and distant tumors in vivo. This study offers new insights into the development of innovative, smart, activatable nano photodrugs to enhance anticancer therapeutic outcomes.