Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1⁺ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

动脉粥样硬化（AS）是全世界心脑血管疾病的主要原因，是由脂质含量积累和慢性炎症引起的。传统策略主要侧重于降脂以控制 AS 进展，从而留下主要不良心血管事件 (MACE) 的残余炎症风险。虽然针对先天免疫的抗炎疗法减少了 MACE，但许多患者仍然面临重大风险。 AS 进展的另一个关键因素是适应性免疫，但其在预防 AS 中的潜在作用仍不清楚。为了研究这一点，我们对患有 AS 斑块的肿瘤患者进行了回顾性队列研究。我们发现抗程序性细胞死亡蛋白 1 (PD-1) 单克隆抗体 (mAb) 可显着减少 AS 斑块大小。通过多组学单细胞分析，我们全面表征了 AS 斑块特异性 PD-1 ⁺ T 细胞，这些细胞具有激活性和促炎性。我们证明，抗 PD-1 mAb 当被骨髓表达的 Fc gamma 受体 (FcγR) 捕获时，会与 T 细胞上表达的 PD-1 相互作用。这种相互作用将抗 PD-1 mAb 转变为替代性 PD-1 配体，抑制 AS 斑块中 PD-1 配体缺陷环境中的 T 细胞功能。此外，我们对接受具有或不具有 Fc 结合能力的抗 PD-1 mAb 治疗的肿瘤患者进行了一项前瞻性队列研究。我们的分析表明，具有 Fc 结合能力的抗 PD-1 mAb 可以有效减少 AS 斑块大小，而不具有 Fc 结合能力的抗 PD-1 mAb 则不能。我们的工作表明，T 细胞靶向免疫疗法可以成为解决人类 AS 的有效策略。