LILRB4 is an immunosuppressive receptor, and its targeting drugs are undergoing multiple preclinical and clinical trials. Currently, the absence of a functional LILRB4 ligand in solid tumors not only limits the strategy of early antibody screening but also leads to the lack of companion diagnostic (CDx) criteria, which is critical to the objective response rate in early-stage clinical trials. Here, we show that galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4, and its ligation induces M-MDSC by activating STAT3 and inhibiting NF-κB. Significantly, Gal-8, but not APOE, can induce MDSC, and both ligands bind LILRB4 noncompetitively. Gal-8 expression promotes in vivo tumor growth in mice, and the knockout of LILRB4 attenuates tumor growth in this context. Antibodies capable of functionally blocking Gal-8 are able to suppress tumor growth in vivo. These results identify Gal-8 as an MDSC-driving ligand of LILRB4, and they redefine a class of antibodies for solid tumors.

LILRB4 是一种免疫抑制受体，其靶向药物正在进行多项临床前和临床试验。目前，实体瘤中缺乏功能性 LILRB4 配体不仅限制了早期抗体筛选的策略，还导致缺乏伴随诊断 （CDx） 标准，这对早期临床试验的客观缓解率至关重要。在这里，我们表明半乳糖凝集素-8 （Gal-8） 是 LILRB4 的高亲和力功能配体，其连接通过激活 STAT3 和抑制 NF-κB 诱导 M-MDSC。值得注意的是，Gal-8 而不是 APOE 可以诱导 MDSC，并且两种配体都非竞争性地结合 LILRB4。Gal-8 表达促进 小鼠体内肿瘤生长，在这种情况下，敲除 LILRB4 会减弱肿瘤生长。能够功能阻断 Gal-8 的抗体能够在体内抑制肿瘤生长 。这些结果确定 Gal-8 是 LILRB4 的 MDSC 驱动配体，并重新定义了一类用于实体瘤的抗体。