SummaryCytotoxic T lymphocytes (CTLs) control tumors via lysis of antigen-presenting targets or through secretion of cytokines such as interferon-γ (IFNG), which inhibit tumor cell proliferation. Improved understanding of CTL interactions within solid tumors will aid the development of immunotherapeutic strategies against cancer. In this study, we take a systems biology approach to compare the importance of cytolytic versus IFNG-mediated cytostatic effects in a murine melanoma model (B16F10) and to dissect the contribution of immune checkpoints HAVCR2, LAG3, and PDCD1/CD274 to CTL exhaustion. We integrated multimodal data to inform an ordinary differential equation (ODE) model of CTL activities inside the tumor. Our model predicted that CTL cytotoxicity played only a minor role in tumor control relative to the cytostatic effects of IFNG. Furthermore, our analysis revealed that within B16F10 melanomas HAVCR2 and LAG3 better characterize the development of a dysfunctional CTL phenotype than does the PDCD1/CD274 axis.