Immunosuppressive myeloid cells hinder immunotherapeutic efficacy in tumors, but the precise mechanisms remain undefined. Here, by performing single-cell RNA sequencing in colorectal cancer tissues, we found tumor-associated macrophages and granulocytic myeloid-derived suppressor cells increased most compared to their counterparts in normal tissue and displayed the highest immune-inhibitory signatures among all immunocytes. These cells exhibited significantly increased expression of immunoreceptor tyrosine-based inhibitory motif-bearing receptors, including SIRPA. Notably, Sirpa^−/− mice were more resistant to tumor progression than wild-type mice. Moreover, Sirpα deficiency reprogramed the tumor microenvironment through expansion of TAM_Ccl8^hi and gMDSC_H2-Q10^hi subsets showing strong antitumor activity. Sirpa^−/− macrophages presented strong phagocytosis and antigen presentation to enhance T cell activation and proliferation. Furthermore, Sirpa^−/− macrophages facilitated T cell recruitment via Syk/Btk-dependent Ccl8 secretion. Therefore, Sirpα deficiency enhances innate and adaptive immune activation independent of expression of CD47 and Sirpα blockade could be a promising strategy to improve cancer immunotherapy efficacy.

免疫抑制性骨髓细胞阻碍肿瘤的免疫治疗效果，但其确切机制仍不清楚。在这里，通过在结直肠癌组织中进行单细胞 RNA 测序，我们发现肿瘤相关巨噬细胞和粒细胞骨髓源性抑制细胞与正常组织中的对应细胞相比增加最多，并且在所有免疫细胞中表现出最高的免疫抑制特征。这些细胞表现出基于免疫受体酪氨酸的抑制性基序受体（包括SIRPA）的表达显着增加。值得注意的是，Sirpa ^−/−小鼠比野生型小鼠对肿瘤进展具有更强的抵抗力。此外，Sirpα 缺陷通过TAM_Ccl8 ^hi和 gMDSC_ H2-Q10 ^hi子集的扩展重新编程肿瘤微环境，显示出强大的抗肿瘤活性。Sirpa ^−/−巨噬细胞表现出强烈的吞噬作用和抗原呈递，以增强 T 细胞的活化和增殖。此外，Sirpa ^−/−巨噬细胞通过 Syk/Btk 依赖性 Ccl8 分泌促进 T 细胞招募。因此，Sirpα 缺陷增强先天性和适应性免疫激活，不依赖于 CD47 的表达，Sirpα 阻断可能是提高癌症免疫治疗效果的一种有前途的策略。