Photoimmunotherapy Meets Systemic Immunotherapy: Molecular Mechanisms, Microenvironmental Remodeling, and Combinatorial Paradigms in Solid Tumors

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.