Bone Marrow Adipocytes in Multiple Myeloma: Emerging Immunometabolic Interactions and Implications for Immunotherapy

Immunotherapy has revolutionized the treatment of multiple myeloma (MM), but durable immune control remains limited, increasing interest in how the bone marrow (BM) microenvironment influences antitumor immunity. BM adipocytes (BMAds) are increasingly recognized as metabolically active components of the BM. This review summarizes the current evidence linking BMAds to myeloma cell survival and immune cell function, particularly T cell activity. It also discusses their potential relevance to monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy. Preclinical studies have shown that myeloma-associated BMAds undergo lipid depletion and acquire inflammatory and senescence-associated secretory features. BM lipid exposure is associated with impaired CD8⁺ T-cell metabolic fitness, whereas leptin receptor activation suppresses invariant natural killer T-cell anti-myeloma activity. Evidence concerning conventional natural killer cells and other immune compartments remains limited. Available clinical evidence is predominantly cross-sectional and therefore does not establish a direct role for BMAds in resistance to current immunotherapies or clarify whether they influence therapeutic target availability or function as clinically relevant bystander targets. Patient- and treatment-related factors, including aging and obesity, may further reshape the adipocytic-stromal and immune landscape of the marrow, potentially modifying local responses to immunotherapy. Future studies combining patient-derived multicellular models with spatial and longitudinal approaches should determine how BMAd-associated metabolic, inflammatory, and adipokine signaling affect immune control and treatment outcomes in MM and whether these processes can be therapeutically modulated.