Targeting of the CD161 Inhibitory Receptor Enhances Bone‐Marrow‐Resident Memory CD8 + T‐Cell‐Mediated Immunity against Multiple Myeloma

Abstract Immune checkpoint inhibitors (ICIs) have transformed the treatment of many solid tumors. Still, their effectiveness in multiple myeloma (MM) remains underwhelming, highlighting the need to explore alternative approaches beyond conventional ICIs. Here, CD161 is identified as a novel inhibitory receptor on bone marrow (BM) tissue resident memory CD8 + T cells (CD8 + TRM), known for their sustained presence and vital role in local immune surveillance in MM BM tumor microenvironments. The CD161–CLEC2D axis, where CD161 interacts with CLEC2D on MM cells, mediates immune suppression and TRM dysfunction. Blocking CD161 enhances TRM function, including tissue residency, proliferation, and antitumor activity. CD161 blockade significantly alleviates chimeric antigen receptor T‐cell (CAR‐T) exhaustion and enhances their antimyeloma function ex vivo. These findings identified the CD161–CLEC2D pathway as a potential novel target for immunotherapy of MM.