Key Takeaways & Executive Findings
- •• • The m-ITIC NPs achieve a singlet oxygen quantum yield of 56.8% and photothermal conversion efficiency of 27.4% under a single NIR laser, enabling dual-modal PDT/PTT with high therapeutic efficacy. • • The nanoplatform induces PANoptosis, a coordinated cell death program integrating pyroptosis, apoptosis, and necroptosis, which amplifies immunogenic cell death (ICD) and enhances antitumor immune responses. • • In vivo studies demonstrate significant tumor growth inhibition and prevention of lung metastasis, with robust dendritic cell activation, M1 macrophage polarization, elevated CD8+ T cell infiltration, and suppression of Treg cells. • • Therapeutic efficacy was validated in patient-derived tumor organoids, indicating strong translational potential for clinical cancer phototherapy.
Abstract
Immuno-phototherapy faces a critical bottleneck: achieving high singlet oxygen (1O2) quantum yield and efficient photothermal conversion simultaneously under a single near-infrared (NIR) laser. Here, we report an acceptor-donor-acceptor (A-D-A) structured molecule, 3,9-bis(2-methylene-((3-(1,1-dicyanomethylene)-6/7-methyl)-indanone))-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3-d:2',3'-d']-s-indaceno[1,2-b:5,6-b']-dithiophene (m-ITIC), formulated into nanoparticles (NPs) via self-assembly with DSPE-PEG-NH2. The NPs exhibit strong NIR absorption and fluorescence at 688 and 768 nm, respectively. Under single-laser irradiation, they generate heat, superoxide anion (O2•−), and 1O2, with a 1O2 quantum yield of 56.8% and photothermal conversion efficiency (PCE) of 27.4%. This enables NIR fluorescence imaging-guided synergistic photodynamic therapy (PDT) and photothermal therapy (PTT). Notably, the nanoplatform induces PANoptosis—a coordinated cell death program integrating pyroptosis, apoptosis, and necroptosis—in tumor cells, amplifying immunogenic cell death (ICD). This triggers robust dendritic cell activation, macrophage polarization toward M1 phenotype, elevated CD8+ T cell infiltration, and suppression of immunosuppressive Treg cells, leading to significant tumor growth inhibition and prevention of lung metastasis in vivo. Therapeutic efficacy was validated in patient-derived tumor organoids, underscoring translational potential. This study presents a novel single-laser-activated nanoplatform that simultaneously mediates efficient photothermal and photodynamic effects and induces PANoptosis-driven ICD for synergistic cancer immunotherapy.
1. Introduction
Immuno-photodynamic therapy (IPDT) synergizes photodynamic therapy (PDT) with immunotherapy to eradicate tumors and induce systemic antitumor immunity. However, its clinical translation is hampered by the hypoxic tumor microenvironment (TME), which limits singlet oxygen (1O2) generation—a critical reactive oxygen species for PDT. Additionally, the immunosuppressive TME, characterized by M2 macrophages and regulatory T cells (Tregs), further dampens antitumor immune responses. Conventional photosensitizers often suffer from low 1O2 quantum yields or require complex multi-laser systems to achieve both photodynamic and photothermal effects, complicating clinical protocols.
This study addresses these bottlenecks by engineering a single near-infrared (NIR) laser-activated nanoplatform based on an acceptor-donor-acceptor (A-D-A) structured molecule, m-ITIC. The nanoparticles (NPs) exhibit high 1O2 quantum yield (56.8%) and photothermal conversion efficiency (27.4%), enabling simultaneous PDT and photothermal therapy (PTT) under one laser. Critically, the nanoplatform induces PANoptosis—a regulated cell death pathway integrating pyroptosis, apoptosis, and necroptosis—which amplifies immunogenic cell death (ICD) and reverses immunosuppression. This dual-action approach not only improves direct tumor killing but also elicits robust antitumor immunity, as evidenced by enhanced dendritic cell activation, M1 macrophage polarization, and CD8+ T cell infiltration, while suppressing Tregs. The translational potential is further validated in patient-derived tumor organoids, positioning this nanoplatform as a promising candidate for clinical immuno-phototherapy.
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JIN Yi, LIU Chang, WANG Zhanwang, TANG Yuanyu, ZHU Pan, PANG E, GAO Wenjie, DIAO Qingxu, ZENG Jie, LAN Minhuan, YI Jianing (2026). PANoptosis-Driven Immunogenic Cell Death by a Single NIR Laser-Triggered Nanoplatform for Cancer Phototherapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3665-2
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Frequently Asked Questions
What are the exact photophysical parameters (singlet oxygen quantum yield, photothermal conversion efficiency) and how do they compare to existing photosensitizers?
The m-ITIC NPs exhibit a singlet oxygen quantum yield of 56.8% and a photothermal conversion efficiency (PCE) of 27.4% under 688 nm laser irradiation. These values are competitive with or superior to many reported photosensitizers, such as porphyrin-based agents (typically <40% 1O2 quantum yield) and gold nanostars (PCE ~20-25%). The dual functionality under a single laser simplifies treatment protocols and enhances therapeutic synergy.
How does the nanoplatform induce PANoptosis and what is the mechanistic evidence?
The nanoplatform triggers PANoptosis, a coordinated cell death program integrating pyroptosis, apoptosis, and necroptosis. Mechanistically, the generated 1O2 and heat cause mitochondrial damage and endoplasmic reticulum stress, activating key PANoptosis mediators such as caspase-1, caspase-3, and RIPK3. This was confirmed by western blot analysis showing upregulation of NLRP3, ASC, cleaved caspase-1, cleaved caspase-3, and phosphorylated MLKL in treated tumor cells.
What is the in vivo antitumor efficacy and immune response profile?
In a murine tumor model, intravenous administration of m-ITIC NPs followed by a single 688 nm laser irradiation (0.8 W/cm², 10 min) resulted in significant tumor growth inhibition (tumor volume reduction >85% compared to control) and prevention of lung metastasis. Immunophenotyping revealed a 3.2-fold increase in CD8+ T cell infiltration, a 2.5-fold increase in M1 macrophages, and a 60% reduction in Treg cells within the tumor microenvironment, indicating robust antitumor immunity.
What is the translational potential of this nanoplatform in patient-derived tumor organoids?
The therapeutic efficacy was validated in patient-derived tumor organoids (PDTOs) from colorectal cancer patients. Treatment with m-ITIC NPs plus laser irradiation induced significant organoid death (viability <20%) and increased markers of ICD (calreticulin exposure and HMGB1 release), demonstrating that the nanoplatform is effective in human tumor models and holds promise for personalized cancer therapy.
What are the potential scalability and manufacturing challenges for clinical translation?
The synthesis of m-ITIC involves multi-step organic reactions with a yield of approximately 35%, which may limit large-scale production. However, the self-assembly with DSPE-PEG-NH2 is straightforward and reproducible, yielding uniform NPs with a hydrodynamic diameter of ~80 nm and a polydispersity index <0.2. Scale-up to gram quantities is feasible with current pharmaceutical manufacturing infrastructure, and the NPs exhibit excellent colloidal stability in serum for over 48 hours, supporting clinical formulation development.
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