# FAPα+ Macrophages Orchestrate Immune Evasion in Multiple Myeloma by Dual Regulation of PD‐L1 and T Cell Senescence

## TL;DR

A specific type of macrophage helps cancer cells avoid the immune system in multiple myeloma, offering a new target for immunotherapies.

## Contribution

FAPα+ macrophages are identified as a novel driver of immune evasion in multiple myeloma through dual regulation of PD-L1 and T cell senescence.

## Key findings

- FAPα+ macrophages are enriched in the bone marrow of MM patients and correlate with tumor burden.
- Depletion of FAPα+ macrophages enhances anti-PD-1/PD-L1 therapy efficacy in MM and other cancer models.
- FAPα stabilizes PD-L1 and induces T cell senescence, promoting immune evasion in multiple myeloma.

## Abstract

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.

Fibroblast activation protein alpha‐positive (FAPα+) macrophages, a distinct subset of multiple myeloma (MM)‐associated macrophages, drive immune evasion in MM through multi‐faceted mechanisms. FAPα physically interacts with vimentin (VIM) and triggers its phosphorylation at the S72 residue, which in turn induces PD‐L1 transcription. Additionally, FAPα sustains PD‐L1 protein stability by preserving its N‐glycosylation and suppressing proteasomal degradation of PD‐L1. Moreover, FAPα+ macrophages secrete soluble FAPα to accelerate T cell senescence, further facilitating MM immune escape. Collectively, these findings identify FAPα+ macrophages as a key mediator of MM immune evasion and a promising therapeutic target for developing novel anti‐MM immunotherapies.