Targeting Folate Receptors for the Detection and Selective Treatment of Cancer: Advanced Precision Oncology in Practice.

The modern era of precision oncology strives to identify novel and selective druggable targets that, on the one hand, achieve efficacious anti-tumor activity, and on the other hand inflict minimal adverse effects to healthy tissues. The realization that both the tumor microenvironment and the tumor immune microenvironment (TIME) modulate tumor progression and response to chemotherapeutics, has pushed tumor-associated immune cells to the forefront as bona fide druggable targets. Based on their unique overexpression pattern on the cell surface of specific human malignancies and suppressor immune cells, folate receptors FRα and FRβ constitute optimal facilitators of noninvasive cancer detection and localization, as well as efficacious selective delivery of potent therapeutic payloads. Along this vein, this review highlights recent advanced strategies utilizing FR-targeting for precise tumor and metastatic lesion localization for guided surgical precision resection, potent anti-cancer efficacy and reprogramming of the suppressive TIME. Notably, these activities were accomplished with minimal side effects to healthy tissues. AZD5335, a recent clinically tested FRα-targeted antibody-drug conjugate carrying a topoisomerase I inhibitor payload, exceeded its predecessors by demonstrating remarkable efficacy against low FRα-expressing tumors as well. Thus, FRs emerge as selective and promising targets for advanced precision oncology of various malignancies including those displaying chemoresistance.