癌症干细胞（CSC）被认为在癌症的发生、进展和复发中至关重要。众所周知，CSC 对癌症治疗具有更强的抵抗力。然而，CSC 与免疫微环境之间的相互作用很复杂且尚未完全了解。在当前的研究中，我们使用单细胞RNA序列（scRNA-Seq，公共数据集）技术来识别CSC的特征。我们发现肺腺癌干细胞群具有高度炎症性，并通过分泌炎症因子，特别是急性期蛋白血清淀粉样蛋白 A (SAA) 来重塑肿瘤微环境。接下来，我们开发了一种离体自体患者来源的类器官（PDO）和外周血单核细胞（PBMC）共培养模型来评估SAA的免疫生物学影响。我们发现SAA不仅通过诱导癌干转化来促进化疗耐药，而且还通过驱动2型免疫来限制抗肿瘤免疫并促进肿瘤纤维化，而α-SAA中和抗体可以限制治疗耐药和肿瘤纤维化。从机制上讲，我们发现SAA诱导的恶性表型依赖于P2X7受体。我们的数据表明，分泌SAA的癌症干细胞具有显着的生物学影响，通过P2X7受体驱动癌症干性转化和2型免疫极化，从而促进治疗耐药和肿瘤纤维化。值得注意的是，α-SAA 中和抗体通过限制这些恶性表型显示出治疗潜力。© 2023。作者。

Cancer stem cells (CSCs) are believed to be crucial in the initiation, progression, and recurrence of cancer. CSCs are also known to be more resistant to cancer treatments. However, the interaction between CSCs and the immune microenvironment is complex and not fully understood. In current study we used single cell RNA sequence (scRNA-Seq, public dataset) technology to identify the characteristic of CSCs. We found that the lung adenocarcinoma cancer stem population is highly inflammatory and remodels the tumor microenvironment by secreting inflammatory factors, specifically the acute phase protein serum amyloid A (SAA). Next, we developed an ex-vivo autologous patient-derived organoids (PDOs) and peripheral blood mononuclear cells (PBMCs) co-culture model to evaluate the immune biological impact of SAA. We found that SAA not only promotes chemoresistance by inducing cancer stem transformation, but also restricts anti-tumor immunity and promotes tumor fibrosis by driving type 2 immunity, and α-SAA neutralization antibody could restrict treatment resistant and tumor fibrosis. Mechanically, we found that the malignant phenotype induced by SAA is dependent on P2X7 receptor. Our data indicate that cancer stem cells secreted SAA have significant biological impact to promote treatment resistant and tumor fibrosis by driving cancer stemness transformation and type 2 immunity polarization via P2X7 receptor. Notably, α-SAA neutralization antibody shows therapeutic potential by restricting these malignant phenotypes.© 2023. The Author(s).