ABSTRACT: Colony-Stimulating Factor-1 Receptor (CSF1R) is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages and bone-resorbing osteoclasts. Mutations of CSF1R have been implicated in neurodegeneration, skeletal anomalies, and cancers. Activation of CSF1R by endogenous cytokine ligation to the ectodomain triggers the autophosphorylation of the intracellular tyrosine kinase domain, and thereafter, activation of several downstream pro-survival kinase cascades, including PI3K, ERK1/2, and JNK. The immunological role of CSF1R in regulating tumor-associate macrophages (TAMs) have been well-documented. TAMs harboring activated CSF1R release tumorigenic cytokines, which further deconditioning tumor microenvironment to a protumoral phenotype. Pharmacological inhibition of CSF1R has emerged as a promising antitumor strategy, with PLX3397 (pexidartinib) been approved by the FDA for the treatment of tenosynovial giant cell tumor in 2019. Research around developing novel small-molecule CSF1R inhibitors, as well as expanding their potential indications, have drawn numerous attentions thenceforward. Herein, we've comprehensively reviewed the latest progression of CSF1R inhibitors under clinical and preclinical studies. Key findings of CSF1R targeted therapies either as monotherapy or combinatorial therapy have also been discussed.

摘要：集落刺激因子 1 受体 (CSF1R) 是一种受体酪氨酸激酶，控制大多数组织驻留巨噬细胞和骨吸收破骨细胞的分化和维持。 CSF1R 突变与神经退行性疾病、骨骼异常和癌症有关。内源性细胞因子与胞外域连接激活 CSF1R 会触发细胞内酪氨酸激酶结构域的自磷酸化，随后激活多个下游促生存激酶级联，包括 PI3K、ERK1/2 和 JNK。 CSF1R 在调节肿瘤相关巨噬细胞 (TAM) 中的免疫学作用已得到充分证明。含有激活的 CSF1R 的 TAM 会释放致瘤细胞因子，进一步使肿瘤微环境失调，形成促肿瘤表型。 CSF1R的药理抑制已成为一种有前途的抗肿瘤策略，PLX3397（pexidartinib）于2019年获得FDA批准用于治疗腱滑膜巨细胞瘤。围绕开发新型小分子CSF1R抑制剂以及扩大其潜在适应症的研究，从此引起了无数人的关注。在此，我们全面综述了CSF1R抑制剂的临床和临床前研究的最新进展。还讨论了 CSF1R 靶向治疗作为单一疗法或联合疗法的主要发现。