Photoimmunotherapy Meets Systemic Immunotherapy: Molecular Mechanisms, Microenvironmental Remodeling, and Combinatorial Paradigms in Solid Tumors
4 affiliations
- 1Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV—IRCCS, 35128 Padua, Italy
- 2Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
- 3Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, 35020 Padua, Italy
- 4Casa di Cura Caminiti, Villa San Giovanni, 89018 Reggio Calabria, Italy
Abstract
Photodynamic therapy (PDT) remains constrained by physical barriers, including strict oxygen dependence, acute hypoxia exacerbation, and limited light penetration depth. While conventional photodynamic therapy (PDT) is strictly oxygen-dependent and limited by light scattering, Near-Infrared Photoimmunotherapy (NIR-PIT) overcomes microenvironmental hypoxia through targeted, oxygen-independent biophysical membrane rupture. However, tissue optical attenuation at 690 nm remains a fundamental physical boundary that necessitates interstitial fiber placement for deep lesions. Concurrently, recent advances in bioengineered nano-photoimmunotherapy (nano-PIT) and organelle-targeted photodynamic/photothermal platforms deliberately execute alternative inflammatory non-apoptotic pathways, such as pyroptosis, cuproptosis, and ferroptosis, and provoke cytosolic leakage of mitochondrial DNA that engages the cGAS-STING innate immune axis. Concurrently, NIR-PIT comprehensively remodels the immunosuppressive tumor microenvironment (TME) by selectively depleting regulatory T cells (Tregs), myeloid-derived suppressor (MDSCs) cells, and cancer-associated fibroblasts (CAFs), thereby deconstructing desmoplastic stroma, lowering interstitial fluid pressure (IFP), and driving the Super-Enhanced Permeability and Retention (SUPR) effect. Photically released mitochondrial DNA further engages the cytosolic cGAS-STING pathway, stimulating type I interferon signaling and dendritic cell cross-presentation. In selected preclinical models, this biophysical collapse promotes immunogenic cell death (ICD) and tumor microenvironment remodeling. When combined with systemic immunotherapies, NIR-PIT has demonstrated the potential to prime antitumor immunity and elicit abscopal responses in responsive syngeneic models; however, this immune conversion is not universal and is heavily constrained by tumor mutational burden, baseline antigen presentation fidelity, and diverse immunosuppressive networks. Translating these paradigms into clinical practice requires advancing 3D microphysiological models, implantable light technologies, and multi-component dosimetry frameworks.
Related
- Bariatric surgery-induced gut microbiota remodeling and innate immune activation: implications for gastrointestinal cancer immunotherapy
- Patient-aware single-cell analysis of fibrovascular remodeling in a predominantly colorectal cancer immunotherapy cohort
- Metabolic Remodeling in Peritoneal Dialysis-Associated Peritoneal Fibrosis: Mechanisms, Candidate Metabolic Signatures, and Therapeutic Perspectives
- SWI/SNF chromatin remodeling complexes in metabolic disorders: integrating tissue-specific epigenetic mechanisms.
- Immune cell-derived exosomes in the tumor microenvironment: mechanisms of immune evasion and emerging therapeutic strategies in cancer immunotherapy
BibTeX
@article{russano2026photoimmunotherapy,
title = {{Photoimmunotherapy Meets Systemic Immunotherapy: Molecular Mechanisms, Microenvironmental Remodeling, and Combinatorial Paradigms in Solid Tumors}},
author = {Francesco Russano and Francesco Callegarin and Davide Brugnolo and Marco Rastrelli and Rocco Caminiti and Giuseppe Sciacca and Daniele Scafuri and Marcodomenico Mazza and Paolo Del Fiore and Luigi Dall’Olmo and Simone Mocellin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219854},
url = {https://www.mdpi.com/1422-0067/27/21/9854},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Photoimmunotherapy Meets Systemic Immunotherapy: Molecular Mechanisms, Microenvironmental Remodeling, and Combinatorial Paradigms in Solid Tumors
AU - Francesco Russano
AU - Francesco Callegarin
AU - Davide Brugnolo
AU - Marco Rastrelli
AU - Rocco Caminiti
AU - Giuseppe Sciacca
AU - Daniele Scafuri
AU - Marcodomenico Mazza
AU - Paolo Del Fiore
AU - Luigi Dall’Olmo
AU - Simone Mocellin
PY - 2026
DA - 2026/11/03
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219854
UR - https://www.mdpi.com/1422-0067/27/21/9854
AB - Photodynamic therapy (PDT) remains constrained by physical barriers, including strict oxygen dependence, acute hypoxia exacerbation, and limited light penetration depth. While conventional photodynamic therapy (PDT) is strictly oxygen-dependent and limited by light scattering, Near-Infrared Photoimmunotherapy (NIR-PIT) overcomes microenvironmental hypoxia through targeted, oxygen-independent biophysical membrane rupture. However, tissue optical attenuation at 690 nm remains a fundamental physical boundary that necessitates interstitial fiber placement for deep lesions. Concurrently, recent advances in bioengineered nano-photoimmunotherapy (nano-PIT) and organelle-targeted photodynamic/photothermal platforms deliberately execute alternative inflammatory non-apoptotic pathways, such as pyroptosis, cuproptosis, and ferroptosis, and provoke cytosolic leakage of mitochondrial DNA that engages the cGAS-STING innate immune axis. Concurrently, NIR-PIT comprehensively remodels the immunosuppressive tumor microenvironment (TME) by selectively depleting regulatory T cells (Tregs), myeloid-derived suppressor (MDSCs) cells, and cancer-associated fibroblasts (CAFs), thereby deconstructing desmoplastic stroma, lowering interstitial fluid pressure (IFP), and driving the Super-Enhanced Permeability and Retention (SUPR) effect. Photically released mitochondrial DNA further engages the cytosolic cGAS-STING pathway, stimulating type I interferon signaling and dendritic cell cross-presentation. In selected preclinical models, this biophysical collapse promotes immunogenic cell death (ICD) and tumor microenvironment remodeling. When combined with systemic immunotherapies, NIR-PIT has demonstrated the potential to prime antitumor immunity and elicit abscopal responses in responsive syngeneic models; however, this immune conversion is not universal and is heavily constrained by tumor mutational burden, baseline antigen presentation fidelity, and diverse immunosuppressive networks. Translating these paradigms into clinical practice requires advancing 3D microphysiological models, implantable light technologies, and multi-component dosimetry frameworks.
SN - 1422-0067
ER -