CD24 as an innate immune checkpoint in solid tumors: biology, biomarker stratification, and therapeutic translation.

CD24 is a glycosylphosphatidylinositol-anchored surface protein frequently overexpressed in solid tumors and increasingly recognized as an innate immune checkpoint that suppresses macrophage-mediated phagocytosis through engagement of Siglec-10 in humans (Siglec-G in mice). Beyond its associations with tumor aggressiveness and stem-like phenotypes, CD24 functions at a critical interface between tumor-intrinsic plasticity and myeloid-driven immune suppression within the tumor microenvironment (TME). Despite growing therapeutic interest, clinical translation of CD24 targeting has been limited by tumor heterogeneity, redundancy among innate immune checkpoints, safety concerns related to physiological CD24 expression, and the absence of functional biomarker frameworks. In this review, we synthesize recent advances in CD24 biology, biomarker-guided stratification strategies, and emerging CD24-directed therapeutic modalities. We highlight unresolved controversies, define key translational challenges, and propose future directions for integrating CD24 targeting into precision immunotherapy strategies tailored to dominant immune resistance mechanisms in solid tumors.