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

Abstract

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.

Heptamethine Cyanine-Loaded Nanomaterials for Cancer Immuno-Photothermal/Photodynamic Therapy: A Review

“…The photothermal and photodynamic effects mediated by HC-loaded nanomaterials can trigger a series of events that are crucial for potentiating the antitumoral immune responses [ 31 , 33 , 35 ]. For this reason, the immuno-PTT/PDT potential of these nanomaterials is being investigated for metastatic cancer treatment [ 32 , 37 , 73 , 74 ].…”

“…Afterward, the primary tumor (i.e., the original tumor) is irradiated with NIR light, and the nanomaterials accumulated in this zone produce a localized temperature increase and/or ROS [ 32 , 71 , 85 ]. Such effects can damage cancer cells and may be sufficiently strong to ablate the primary tumor [ 32 , 86 , 87 ].…”

“…Afterward, the primary tumor (i.e., the original tumor) is irradiated with NIR light, and the nanomaterials accumulated in this zone produce a localized temperature increase and/or ROS [ 32 , 71 , 85 ]. Such effects can damage cancer cells and may be sufficiently strong to ablate the primary tumor [ 32 , 86 , 87 ]. As importantly, the nanomaterials’ photothermal/photodynamic effects can also (i) relieve tumor hypoxia [ 31 , 32 ], (ii) release TAAs and DAMPs (e.g., exposure of calreticulin (CRT) on cancer cells’ membrane, release ATP and high mobility group box 1 protein (HMGB1)) [ 33 , 34 ], and (iii) induced a pro-inflammatory response ( Figure 2 ) [ 35 , 36 ].…”

“…For instance, Zhao and co-workers demonstrated that PTT/PDT generated by ICG-incorporating polymeric nanostructures induced CRT exposure and HMGB1 and ATP release, leading to about 2.20-fold higher dendritic cell (DC) maturation (when compared to the non-irradiated nanostructures and the control group) [ 32 ]. Moreover, the photothermal heating produced by these nanostructures also improved tumor oxygenation.…”

“…These photo-triggered effects not only induced direct damage on the cancer cells at the primary site but can also (i) relieve tumor hypoxia [ 30 , 31 , 32 ], (ii) release tumor-associated antigens (TAAs) and danger-associated molecular patterns (DAMPs) [ 32 , 33 , 34 ], and (iii) induced a pro-inflammatory response [ 33 , 35 , 36 ]. These events will then synergize with the activity of immunostimulants (toll-like receptor (TLR) agonists) and immune checkpoint inhibitors (ICIs; e.g., IDO1 inhibitors, CTLA-4 and PD-1/PD-L1 blockers) [ 37 , 38 , 39 ].…”