For over half a century, the three main pillars of conventional cancer therapy are surgery, chemotherapy, and radiotherapy. However, these treatment methods have inherent limitations, as they inevitably cause severe damage to normal cells, particularly immune cells. The discovery and development of immunotherapy show promising clinical applications. Nonetheless, immunotherapy is a double-edged sword, often leading to the occurrence of immune-related adverse events (irAEs) because of off-target effects. Therefore, the current focus in cancer research is to explore treatment strategies that can activate local immune responses while enhancing tumor specificity.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel tumor therapy, and it depends on a single antibody-photo absorber conjugate (APC), which combines a monoclonal antibody (McAb) targeted on tumor features with IRDye700DX (IR700). Except for its specific antitumor mechanisms, a unique aspect of NIR-PIT is its direct impact on blood drug delivery. The super-enhanced permeability and retention (SUPR) effects facilitate the rapid leakage of drugs into the tumor, favoring the induction of cytotoxic effects. However, the presence of the “binding site barrier” indicates that using antibodies with low affinity or targeting antibodies with low antigen expression may promote a more even distribution of APCs within the tumor parenchyma. In recent years, researchers have investigated the use of different targeting segments in NIR-PIT, enhancing the tumor immunogenicity, targeting ability, stability, and flexibility of NIR-PIT drugs. This approach has shown considerable potential for application in various types of tumors, with some related clinical trials yielding satisfactory results.

Studies have shown a close association between the suppressive tumor microenvironment (TME) and the growth and progression of cancer. In recent years, the targets of APCs in NIR-PIT have expanded to surface proteins of non-tumor cells in TME. The combination therapy of NIR-PIT with immune checkpoint blockade (ICB) has also shown promising experimental results. The development and continuous improvement of optical devices also facilitate the monitoring and evaluation of the therapeutic effects of NIR-PIT. Therefore, it is necessary to summarize previous relevant research to provide a rational reference for the clinical research and application of NIR-PIT.

The primary mechanism through which NIR-PIT exerts its cytotoxic effects is via a photochemical reaction from IR700. Under near-infrared light, IR700 in APCs undergoes a photocatalytic transformation, changing its chemical properties from hydrophilic to hydrophobic, and aggregating in an aqueous solution. This process leads to the denaturation of the cell membrane antigens bound to it, physical damage to the cell membrane and cell rupture, increased transmembrane water flow, and cell death (Fig.1). Simultaneously, the rapid release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) during NIR-PIT induces immunogenic cell death (ICD), and subsequently, activates the antitumor immune response of the host, enhancing the activation of systemic immune responses to attack other cancer cells and further amplifying the therapeutic effects of NIR-PIT (Fig.2). Current NIR-PIT treatment strategies targeting key components in TME, including immune inhibitory cells (Tregs and MDSCs), cancer-associated fibroblasts (CAFs), and blood vessels, are listed in Table 1. The design principles of APCs and relevant experimental results are also presented. Subsequently, the combined therapeutic strategies and efficacy of immune checkpoint inhibitors with NIR-PIT targeting different cell surface proteins are elucidated. Given the heterogeneity of immune cell populations in different tumors, the choice of ICBs can be based on the expression levels of specific immune checkpoint molecules in their respective tumors.

In addition, the progress of clinical trials related to NIR-PIT is summarized, demonstrating that cetuximab-IR700 (RM-1929) can elicit effective antitumor responses in patients with locally recurrent HNSCC where conventional clinical treatments are less effective. Furthermore, the SUPR effect can be quantified using indocyanine green (ICG)-fluorescence and magnetic resonance imaging (MRI) contrast agents to monitor and identify the viability of NIR-PIT. 18F-fluorode-oxyglucose positron emission tomography (18F-FDG-PET), fluorescence lifetime imaging, and bioluminescence imaging can evaluate acute NIR-PIT treatment in preclinical studies. Moreover, the micro distribution of the NIR-PIT agent and its therapeutic effects is monitored using a two-channel fluorescence fiber-imaging system and two-photon microscopy with and without a microprism. The tumoricidal effects and hemodynamic changes induced by NIR-PIT can be monitored by ¹³C MRI, blood oxygenation level dependent (BOLD) MRI, and photoacoustic imaging.

The current investigation of NIR-PIT is relatively limited. In summary, the limitations of replicating IRdye700-McAb conjugates in NIR-PIT, the penetration and uniformity of near-infrared light irradiation, differences in the types and expression of target molecules in different types of tumors, and the safe range of APC dosage in NIR-PIT still require detailed investigations.

Extensive in vitro and in vivo models study on NIR-PIT have been conducted for various types of tumors, with promising therapeutic outcomes. With its broad and flexible application scope, and various approaches to enhance its efficacy, NIR-PIT has significant potential as a valuable method for cancer treatment.