γ干扰素（IFNγ）是一种重要的抗肿瘤细胞因子，对不同细胞类型具有不同的作用。IFNγ在肿瘤中的全局效应取决于它作用的细胞类型和其传播的空间范围。在不同情境下，已报道的IFNγ传播测量结果差异巨大，从最近邻信号到整个肿瘤的灌注都有。本文应用理论考量以及体外和体内实验的方法来研究黑色素瘤中的IFNγ传播。我们观察到在三维小鼠黑色素瘤细胞培养物和人类肿瘤中，有空间限制的IFNγ信号系统产生基因表达的细胞异质性，并改变受影响细胞对T细胞杀伤的易感性。只有当IFNγ产生的T细胞局部密度较高，使得这些空间限制的信号系统重叠时才会出现广泛的IFNγ信号。我们测得B16小鼠黑色素瘤培养物和人类原发性皮肤黑色素瘤中IFNγ传播的长度尺度为约30至40微米。我们的结果与IFNγ传播受简单扩散-消耗模型控制的观点一致，并为T细胞的空间组织如何对炎症信号、基因表达和免疫介导的清除产生肿瘤内异质性提供了见解。实体肿瘤通常被视为多样化的细胞“邻域”的集合：我们的工作为这种非遗传的细胞变异性提供了一个通用的解释，因为免疫介质的传播受限。

Interferon-γ (IFNγ) is a critical antitumor cytokine that has varied effects on different cell types. The global effect of IFNγ in the tumor depends on which cells it acts upon and the spatial extent of its spread. Reported measurements of IFNγ spread vary dramatically in different contexts, ranging from nearest-neighbor signaling to perfusion throughout the entire tumor. Here, we apply theoretical considerations to experiments both in vitro and in vivo to study the spread of IFNγ in melanomas. We observe spatially confined niches of IFNγ signaling in 3-D mouse melanoma cultures and human tumors that generate cellular heterogeneity in gene expression and alter the susceptibility of affected cells to T cell killing. Widespread IFNγ signaling only occurs when niches overlap due to high local densities of IFNγ-producing T cells. We measured length scales of ~30 to 40 μm for IFNγ spread in B16 mouse melanoma cultures and human primary cutaneous melanoma. Our results are consistent with IFNγ spread being governed by a simple diffusion-consumption model and offer insight into how the spatial organization of T cells contributes to intratumor heterogeneity in inflammatory signaling, gene expression, and immune-mediated clearance. Solid tumors are often viewed as collections of diverse cellular "neighborhoods": Our work provides a general explanation for such nongenetic cellular variability due to confinement in the spread of immune mediators.