Dual Regulatory Functions and Therapeutic Potential of CD48 in Tumor Immunity

Cluster of differentiation 48 (CD48) is a glycosylphosphatidylinositol-anchored member of the signaling lymphocyte activation molecule (SLAM) family that is predominantly expressed on hematopoietic cells and regulates immune-cell communication through 2B4 (CD244) and CD2. This narrative review critically summarizes the context-dependent role of CD48 in tumor immunity, with emphasis on the distinction between activating trans-interactions and potentially inhibitory cis-interactions. Evidence from hematologic malignancies and selected solid tumors indicates that CD48 may support antitumor immunity by facilitating natural killer (NK) cells activation, CD8⁺ T-cell co-stimulation, immune synapse formation, and effector cytokine production. Conversely, loss of CD48 expression, sustained CD48-2B4 engagement, altered ligand density, and suppressive myeloid-rich tumor microenvironment (TME) may contribute to immune escape or NK cells dysfunction. Current therapeutic concepts, including anti-CD48 monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, engineered NK/T cells, and epigenetic restoration of CD48 expression, remain largely preclinical and require cautious interpretation. Major translational barriers include broad CD48 expression on normal hematopoietic populations, soluble CD48 (sCD48) interference, uncertain biomarker standardization, and the risk that forced activation in dense solid tumors may reinforce cis-inhibitory signaling rather than improve cytotoxicity. Future studies should define tumor-type-specific signaling states, quantify sCD48, integrate spatial and single-cell approaches, and evaluate rational combinations with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade in mechanism-driven models before clinical translation. This review aims to critically evaluate the dual regulatory roles of CD48 in tumor immunity, distinguish between activating trans-interactions and potentially inhibitory cis-interactions across different tumor types, and assess the translational potential and challenges of CD48-targeted immunotherapeutic strategies.