Near Infrared Photoimmunotherapy for Lung Cancer: Recent Development and Perspective

Lung cancer is the leading cause of cancer mortality worldwide, and despite advances in surgery, chemotherapy, radiotherapy, and immunotherapy, challenges persist due to off-target toxicity and limited specificity. Photodynamic therapy (PDT), a minimally invasive treatment using photosensitizers and light to induce ROS-mediated cell death, has been explored for early-stage lung cancer; however, its clinical utility remains limited by poor tissue penetration, nonspecific photosensitizer uptake, and oxygen dependence.

Near-infrared photoimmunotherapy (NIR-PIT) is a highly specific cancer treatment that overcomes many limitations of conventional PDT. It employs antibody-photoabsorber conjugates, such as monoclonal antibodies linked to IRDye700DX, which bind selectively to cancer cell surface antigens and are activated by 690-nm NIR light. This illumination induces a unique, non-ROS-dependent cell death, "photochemosis", marked by immediate physical disruption of cancer cell membranes. Beyond direct cytotoxicity, NIR-PIT elicits robust immunogenic cell death, promotes systemic antitumor immunity, and permits repeated treatment cycles without compromising safety. The air-rich lung environment and deep penetration of NIR light make lung cancer an ideal NIR-PIT candidate. Advances in light-delivery devices-including endoscopic catheters, flexible LED systems, and endovascular therapy-based technologies-have greatly improved the feasibility of targeting deep pulmonary lesions for clinical implementation. Moreover, the modular design of NIR-PIT allows adaptation to diverse tumor targets, including EGFR and components of the tumor microenvironment, broadening its applicability.

In this review, we provide a comprehensive overview of the mechanisms, advantages, and recent technological innovations of NIR-PIT, with a focus on its potential as a transformative therapeutic approach for lung cancer.