结直肠癌 (CRC) 仍然是全球重大的医疗负担，其特点是肥胖和慢性炎症之间复杂的相互作用。虽然结直肠癌、肥胖和脂质代谢改变之间的关系尚不完全清楚，但有证据表明它们之间存在联系。在这项研究中，我们假设脂质代谢失调会导致结直肠癌中泡沫细胞 (FC) 的局部积累，进而破坏抗肿瘤免疫监视。通过数字病理学对受 T2-T4 结直肠癌影响的患者的肿瘤浸润 FC 和 CD8 进行量化N 期接受根治性前期手术 (n=65) 并与患者的临床结果相关。对 CRC 组织进行多参数高分辨率流式细胞术分析和批量 RNAseq，以评估与 FC 积累相关的免疫细胞浸润的表型和转录组程序。使用脂质吞噬巨噬细胞的体外人体模型探讨了 FC 的免疫抑制作用以及 FC 相关转化生长因子-β (TGF-β) 和抗 PD-L1 抑制的机制研究。FC（大型 CD68 Bodipy 巨噬细胞） ）在 CRC 样本的肿瘤边缘积累。 FChigh 肿瘤表现出 CD8 T 细胞减少和调节性 T 细胞 (Treg) 增加。功能转录谱描绘了一种免疫抑制环境，其特征是干扰素γ、记忆性CD8 T细胞和活化巨噬细胞减少，反映了T细胞耗竭和Treg富集增加。此外，FChigh肿瘤表型与标准临床因素无关，但与高体重指数（BMI）和血浆饱和脂肪酸水平相关。在 CD8low 肿瘤中，FChigh 表型与 8.6% 的 3 年无病生存率相关，而 FClow 为 28.7%（p=0.001）。体外研究表明，FC以TFG-β依赖性方式显着影响CD8增殖，而抑制TGF-β FC相关因子可恢复抗肿瘤免疫。FC通过TGF-β相关途径发挥免疫抑制活性，从而产生CD8 -排除微环境并识别原发性结直肠癌患者预后较差的免疫抑制肿瘤。 FC 与患者 BMI 和血脂异常的关联可能可以解释 CRC 与肥胖的联系，并在这种特定的临床环境中提供新颖的治疗和预防观点。© 作者（或其雇主）2024。CC 允许重复使用BY-NC。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Colorectal cancer (CRC) remains a significant healthcare burden worldwide, characterized by a complex interplay between obesity and chronic inflammation. While the relationship between CRC, obesity and altered lipid metabolism is not fully understood, there are evidences suggesting a link between them. In this study, we hypothesized that dysregulated lipid metabolism contributes to local accumulation of foam cells (FC) in CRC, which in turn disrupts antitumor immunosurveillance.Tumor infiltrating FC and CD8+ were quantified by digital pathology in patients affected by T2-T4 CRC with any N stage undergoing radical upfront surgery (n=65) and correlated with patients' clinical outcomes. Multiparametric high-resolution flow cytometry analysis and bulk RNAseq of CRC tissue were conducted to evaluate the phenotype and transcriptomic program of immune cell infiltrate in relation to FC accumulation. The immunosuppressive effects of FC and mechanistic studies on FC-associated transforming growth factor-beta (TGF-β) and anti-PD-L1 inhibition were explored using an in-vitro human model of lipid-engulfed macrophages.FC (large CD68+ Bodipy+ macrophages) accumulated at the tumor margin in CRC samples. FChigh tumors exhibited reduced CD8+ T cells and increased regulatory T cells (Tregs). Functional transcriptional profiling depicted an immunosuppressed milieu characterized by reduced interferon gamma, memory CD8+ T cells, and activated macrophages mirrored by increased T-cell exhaustion and Treg enrichment. Furthermore, FChigh tumor phenotype was independent of standard clinical factors but correlated with high body mass index (BMI) and plasma saturated fatty acid levels. In CD8low tumors, the FChigh phenotype was associated with a 3-year disease-free survival rate of 8.6% compared with 28.7% of FClow (p=0.001). In-vitro studies demonstrated that FC significantly impact on CD8 proliferation in TFG-β dependent manner, while inhibition of TGF-β FC-related factors restored antitumor immunity.FC exert immunosuppressive activity through a TGF-β-related pathway, resulting in a CD8-excluded microenvironment and identifying immunosuppressed tumors with worse prognosis in patients with primary CRC. FC association with patient BMI and dyslipidemia might explain the link of CRC with obesity, and offers novel therapeutic and preventive perspectives in this specific clinical setting.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.