B2M (beta-2-microglobulin) is a critical light chain component of MHC class I molecules essential for antigen presentation to the immune system 1. As part of the class I complex, B2M facilitates the presentation of peptide antigens required for CD8+ T cell recognition 2. Beyond its canonical immunological role, B2M exhibits unexpected functions in neurological contexts, acting as an endogenous NMDAR antagonist that impairs synaptic function when elevated systemically, contributing to cognitive deficits observed in Down syndrome 3. In cancer biology, B2M demonstrates dual roles. Loss-of-function mutations in B2M represent a major immune evasion mechanism, reducing MHC class I-mediated antigen presentation and enabling tumors to escape CD8+ T cell surveillance 2. Conversely, in glioblastoma, B2M promotes tumor progression through PI3K/AKT/MYC-dependent maintenance of cancer stem cells and paracrine induction of immunosuppressive M2-like macrophage polarization 4. Clinically, B2M manipulation offers therapeutic opportunities. Genetic deletion of B2M in allogeneic CAR-T cells and iPSC-derived therapies requires complementary ablation of adhesion ligands CD54 and CD58 to prevent NK cell-mediated rejection 5. Additionally, B2M-deficient tumors with intact neoantigens remain responsive to immunotherapy through γδ T cell-mediated cytotoxicity 6, suggesting compensatory immune mechanisms.