Obesity induces PD-1 on macrophages to suppress anti-tumour immunity. Nature Obesity is a leading risk factor for progression and metastasis of many cancers, yet can in some cases enhance survival and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-1. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8 T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity. 10.1038/s41586-024-07529-3

Ciprofloxacin promotes polarization of CD86+CD206‑ macrophages to suppress liver cancer. Fan Mengtian,Chen Sicheng,Weng Yaguang,Li Xian,Jiang Yingjiu,Wang Xiaowen,Bie Mengjun,An Liqin,Zhang Menghao,Chen Bin,Huang Gaigai,Wu Jinghong,Zhu Mengying,Shi Qiong Oncology reports Gut microbiota can promote tumor development by producing toxic metabolites and inhibiting the function of immune cells. Previous studies have demonstrated that gut microbiota can reach the liver through the circulation and promote the occurrence of liver cancer. Ciprofloxacin, an effective broad‑spectrum antimicrobial agent, can promote cell apoptosis and regulate the function of immune cells. As an important part of the tumor microenvironment, macrophages play an important role in tumor regulation. The present study demonstrated that the treatment of macrophages with ciprofloxacin was able to promote the production of interleukin‑1β, tumor necrosis factor‑α and the polarization of CD86+CD206‑ macrophages, while inhibiting the polarization of CD86‑CD206+ macrophages. This transformation may help macrophages promote tumor cell apoptosis, inhibit tumor cell proliferation, reduce metastasis and downregulate the phosphoinositide 3‑kinase/AKT signaling pathway in liver cancer cell lines. In vivo experiments demonstrated that macrophages treated with ciprofloxacin inhibited the growth of subcutaneous implanted tumors in nude mice. In conclusion, the findings of the present study indicated that ciprofloxacin may inhibit liver cancer by upregulating the expression of CD86+CD206‑ macrophages. This study further revealed the biological mechanism underlying the potential value of ciprofloxacin in antitumor therapy and provided new targets for the treatment of liver cancer. 10.3892/or.2020.7602