FAPα(+) Macrophages Orchestrate Immune Evasion in Multiple Myeloma by Dual Regulation of PD-L1 and T Cell Senescence.

Multiple myeloma (MM) is a hematologic malignancy driven by clonal expansion of malignant plasma cells. Despite the long-term disease control achieved with immunotherapies in some patients, treatment resistance remains a major cause of disease relapse. Accumulating evidence highlights the tumor immune microenvironment, especially macrophages, as a key contributor to immunotherapy failure in MM. Herein, we identified a subset of MM-associated macrophages with high expression of fibroblast activation protein alpha (FAPα), defined as FAPα(+) macrophages. Clinical data showed that FAPα(+) macrophages were enriched in the bone marrow versus peripheral blood of MM patients, and their abundance positively correlated with tumor burden. In MM mouse models, depletion of FAPα(+) macrophages significantly boosted the efficacy of anti-PD-1/PD-L1 antibody therapy but not anti-CTLA-4 therapy; this combinatorial strategy also exerted enhanced anti-tumor effects in EL4 lymphoma and CT26 colorectal carcinoma models. Mechanistically, FAPα stabilized PD-L1 expression by maintaining its N-glycosylation and inhibiting proteasomal degradation, and induced PD-L1 synthesis via promoting vimentin (VIM) phosphorylation at the S72 residue. Additionally, FAPα(+) macrophages accelerated T cell senescence by secreting soluble FAPα. Collectively, our findings demonstrate that FAPα(+) macrophages mediate MM immune evasion via dual mechanisms, positioning them as promising therapeutic targets to potentiate anti-tumor immunotherapies.