Oncofetal antigens as emerging targets in chimeric antigen receptor (CAR)-T cell-based immunotherapies: opportunities and challenges

Abstract

Oncofetal antigens are emerging targets for chimeric antigen receptor (CAR)-based immunotherapies due to their developmentally restricted expression and frequent re-emergence in malignant cells. These antigens are tightly linked to cellular plasticity, stem-like programs, immune evasion, and resistance to cytotoxic therapies, making them biologically compelling targets. Multiple oncofetal antigens have entered early-phase clinical trials as CAR-T cell targets with promising results in several cancers including neuroblastoma and diffuse midline gliomas. However, antitumor efficacy in most solid malignancies has thus far been modest. This reflects shared obstacles, including low-level expression in normal tissues, intratumoral antigen heterogeneity, immune suppression within the tumor microenvironment, CAR-T cell exhaustion, and limited persistence. In this Mini-Review, we discuss the biological foundations of oncofetal antigen expression, synthesize clinical and pre-clinical experience targeting these antigens with CAR-T cell therapies, and highlight emerging engineering and combination strategies designed to overcome current limitations. We propose that integrating principles from developmental biology, tumor evolution, and immuno-engineering will be essential to unlocking the therapeutic potential of oncofetal antigen-directed CAR-T therapies in solid tumors.