Immune checkpoint inhibitors have shown success in treating a subset of patients with certain late-stage cancers. However, these treatments fail in many other patients, due to mechanisms that have yet to be fully characterized. The process of T cell exhaustion, by which T cells become dysfunctional in response to extended exposure to antigen, has been implicated in immunotherapy resistance. Single-cell RNA sequencing (scRNA-seq) produces an abundance of data to analyze this process, facilitating insights into cellular processes related to treatment efficacy. However, due to the complexity of the process, contributions of other cell types to a process within a single cell type cannot be simply inferred. These results demonstrate that our analysis framework can identify potential mechanisms driving key cellular processes implicated in the failure of cancer immune checkpoint inhibitors. The framework can be applied to all cell types in the tumor immune microenvironment, expanding our understanding of key biological processes that underpin the effective treatment of cancer.