Tumor Suppression by Anti-Fibroblast Activation Protein Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts

Simple Summary Cancer-associated fibroblasts (CAFs) are a key pro-tumorigenic cell type in the tumor microenvironment; however, treatments targeting these cells have shown limited clinical efficacy. In this study, we examined the therapeutic efficacy of CAF depletion using near-infrared photoimmunotherapy (NIR-PIT), a novel technique that selectively targets and depletes specific cells within a tumor. In two tumor models (lung, mammary) with immune-competent mice, selective depletion of fibroblast activation protein (FAP)-expressing cells using NIR-PIT induced interferon-gamma production in tumor-infiltrating CD8 T and natural killer cells and successfully suppressed tumor growth and reduced lung metastasis in the mammary model. These findings highlight the role of CAFs in supporting tumor growth and introduce a promising therapeutic approach for selectively eliminating immunosuppressive FAP+ cells within the tumor microenvironment.Abstract Cancer-associated fibroblasts (CAFs) constitute a prominent cellular component of the tumor stroma, with various pro-tumorigenic roles. Numerous attempts to target fibroblast activation protein (FAP), a highly expressed marker in immunosuppressive CAFs, have failed to demonstrate anti-tumor efficacy in human clinical trials. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor therapy that utilizes an antibody-photo-absorbing conjugate activated by near-infrared light. In this study, we examined the therapeutic efficacy of CAF depletion by NIR-PIT in two mouse tumor models. Using CAF-rich syngeneic lung and spontaneous mammary tumors, NIR-PIT against FAP or podoplanin was performed. Anti-FAP NIR-PIT effectively depleted FAP+ CAFs, as well as FAP+ myeloid cells, and suppressed tumor growth, whereas anti-podoplanin NIR-PIT was ineffective. Interferon-gamma production by CD8 T and natural killer cells was induced within hours after anti-FAP NIR-PIT. Additionally, lung metastases were reduced in the treated spontaneous mammary cancer model. Depletion of FAP+ stromal as well as FAP+ myeloid cells effectively suppressed tumor growth in bone marrow chimeras, suggesting that the depletion of both cell types in one treatment is an effective therapeutic approach. These findings highlight a promising therapy for selectively eliminating immunosuppressive FAP+ cells within the tumor microenvironment.