FAPα+CAFs: Targeting the Tumor Microenvironment for Revolutionary Cancer Therapies

Background: Within the tumor microenvironment (TME), (FAPα+CAFs) referred to as Cancer-Associated Fibroblasts (CAFs) that express Fibroblast Activation Protein α (FAPα) have gained significant attention for their unique diagnostic, prognostic, and therapeutic implications across several types of cancers; including epithelial, breast, pancreatic, ovarian, lung, and colorectal cancers. FAPα is a serine protease in nature, frequently expressed in the stroma of epithelial cancers and is minimally expressed in normal tissues, making it an attractive diagnostic target for cancerspecific interventions. Methods: Relevant studies published within the past decade were systematically checked via Google Scholar, ResearchGate, PubMed, Web of Science, and Scopus mentioning FAPα biology and its potential therapeutic applications in cancer. Additionally, clinical trials were retrieved from ClinicalTrials. gov. Results: Various drugs targeting FAPα, such as the FAPI series (FAPI-04, FAPI-42, FAPI-46, FAPI- 74), RPS-309, and 68Ga-FAP-2286, have shown promising results in cancer imaging, with high tumor uptake and sensitivity, especially in urothelial and pancreatic cancers (tumor uptake exceeding 5% ID/g, 68Ga-FAP-2286 demonstrated 100% tumor rejection in mouse models). Furthermore, 68Ga-FAP-74-PET and 177Lu-LNC1004, when combined with anti-PD-L1 therapy, demonstrated complete tumor elimination in mouse models (tumor inhibition and 100% rejection observed in MC38/NIH3T3-FAP tumor xenografts). Additionally, FAP-targeted agents like FAP5-DM1 (inhibited tumor growth and produced complete remission in xenograft models) and the FAPtau-MT vaccine (three-fold increase in survival time in mice) have been effective in improving immune responses and enhancing T-cell activity against tumors. AntiFAP-mGITRL fusion proteins have shown strong Tcell stimulation, leading to increased IFN-gamma and IL-2 production (100-fold increase in effectiveness in suppressing Tregs). FAP-targeted CAR-T cells have shown potential in improving tumor treatment outcomes by reducing immune suppressor cells (enhanced survival of CD8+ T cells in tumor tissue). The 68Ga/177Lu-LNC1004 exhibited prolonged tumor retention and higher absorption in tumor xenografts. Currently, around 40 clinical trials are ongoing (awaiting final results), exploring a variety of FAPα-targeted therapies, including novel imaging agents, vaccines, and immunotherapies. Conclusion: FAPα+CAFs expression correlates with poor prognosis in several malignancies, making them a valuable biomarker for cancer progression, as well as an emerging therapeutic target offering a new avenue for innovative cancer therapies. Despite these advancements, the use of novel drug delivery systems and long-term toxicity evaluation studies could redefine the future of FAPα-targeted therapies in cancer care.