Macrophage sensitivity to reprogramming by bexmarilimab is shaped by the tumor microenvironment [scRNA-Seq]

Tumor-associated macrophages (TAMs) adapt to the tumor microenvironment (TME), either aiding cancer eradication or promoting tumor growth and immune evasion. To manipulate TAMs therapeutically, a deep understanding of their interaction with the TME is essential. This study exploits a breast cancer patient-derived explant culture (PDEC) model to predict TMEs responsive to bexmarilimab, a macrophage reprogramming therapy showing clinical benefit in various solid tumors. The PDEC model captured key aspects of bexmarilimab's action, validated a gene signature for predicting treatment sensitivity, and characterized responses in both tumor and adjacent cancer-free tissue. We identified three distinct treatment responses shaped by the local TME and macrophage phenotype, origin and localization. The inflammatory state of the TME was detected as the primary factor defining response to bexmarilimab. These findings emphasize the need for patient selection to maximize bexmarilimab's efficacy, particularly in immunologically cold tumors lacking late-stage activated TAMs and reveal the complexity of TAM targeting in cancer. scRNA-seq analysis of paired breast cancer tumor and adjacent cancer-free tissues.肿瘤相关巨噬细胞（Tumor-associated macrophages, TAMs）可适配肿瘤微环境（Tumor microenvironment, TME），既能协助清除癌细胞，也可促进肿瘤生长与免疫逃逸。若要通过治疗手段调控TAMs，深入解析其与TME的相互作用至关重要。本研究借助乳腺癌患者来源外植体培养（breast cancer patient-derived explant culture, PDEC）模型，预测可对贝沙莫利单抗（bexmarilimab）产生应答的TME；贝沙莫利单抗作为一种巨噬细胞重编程治疗药物，在多种实体瘤中已展现临床获益。该PDEC模型捕捉到了贝沙莫利单抗作用的关键特征，验证了可用于预测治疗敏感性的基因特征，并解析了肿瘤组织与癌旁正常组织中的应答情况。本研究鉴定出三种由局部TME、巨噬细胞表型、起源及定位所塑造的差异化治疗应答类型，发现TME的炎症状态是决定贝沙莫利单抗应答的核心因素。上述研究结果强调，需通过患者筛选以最大化贝沙莫利单抗的治疗效果，尤其针对缺乏晚期活化TAMs的免疫冷肿瘤；同时也揭示了癌症中靶向TAM治疗的复杂性。本研究对配对的乳腺癌肿瘤组织与癌旁正常组织开展了单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）分析。