Tailoring Aggregation Extent of Photosensitizers to Boost Phototherapy Potency for Eliciting Systemic Antitumor Immunity

Phototherapy is effective for triggering the immunogenic cell death (ICD) effect. However, its efficacy is limited by low 1O2 generation and photothermal conversion efficacy due to two irreconcilable obstacles, namely the aggregation‐caused‐quenching (ACQ) effect and photobleaching. In this work, a discretely integrated nanofabrication (DIN) platform (Pt‐ICG/PES) is developed by facile coordination coassembly of cisplatin (Pt), photosensitizer molecules (indocyanine green (ICG)), and polymeric spacer (p(MEO2MA‐co‐OEGMA)‐b‐pSS (PES)). By controlling the ICG/PES feeding ratio, the aggregation of ICG can be easily tailored using PES as an isolator to balance the ACQ effect and photobleaching, thereby maximizing the phototherapy potency of Pt‐ICG/PES. With the optimized ratio of each component, Pt‐ICG/PES integrates the complementarity of photodynamic therapy, photothermal therapy, and chemotherapeutics to magnify the ICD effect, exerting a synergistic antitumor immunity‐promoting effect. Additionally, temperature‐sensitive PES enables photothermally guided drug delivery. In a tumor‐bearing mouse model, Pt‐ICG/PES elicits effective release of danger‐associated molecular patterns, dendritic cell maturation, cytotoxic T lymphocytes activation, cytokine secretion, M2 macrophage repolarization, and distal tumor suppression, confirming the excellent in situ tumor ICD effect as well as robust systematic antitumor immunity. Ultimately, a versatile DIN strategy is developed to optimize the phototherapeutic efficacy for improving antitumor effects and strengthening systemic antitumor immunity. A discretely integrated nanofabrication platform (named Pt‐ICG/PES) is reported to boost phototherapy potency and antitumor immunity. Tailoring the aggregation extent of indocyanine green (ICG) to an optimized state can simultaneously relieve photobleaching and aggregation‐caused‐quenching effects, maximizing phototherapy efficiency. Equipped with photodynamic therapy/photothermal therapy/chemotherapy, Pt‐ICG/PES magnifies immunogenic cell death effect, exerting synergistic promotion effect of antitumor immunity.