与细胞固有特性相结合，肿瘤微环境中的相互作用可调节治疗反应。我们利用单细胞空间转录组学来剖析与新辅助化疗和放疗相关的人类胰腺癌中多细胞邻域的重塑和细胞间相互作用。我们开发了空间约束最佳运输相互作用分析（SCOTIA），这是一种具有成本函数的最佳运输模型，其中包括空间距离和配体受体基因表达。我们的结果发现，癌症相关成纤维细胞和恶性细胞之间的配体-受体相互作用在治疗后发生显着变化，这得到了正交数据集（包括离体肿瘤共培养系统）的支持。我们发现白细胞介素 6 家族信号传导的富集在功能上赋予化疗耐药性。总体而言，这项研究表明，使用单细胞空间转录组学对肿瘤微环境进行表征可以识别可能在治疗耐药性出现中发挥作用的分子相互作用，并提供基于空间的分析框架，可广泛应用于其他环境.© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.