Over the past decade, a rapidly growing interest has been in delineating the prognostic value of tumor-infiltrating lymphocytes. Recent reports highlight the importance of integrating tumor-infiltrating T cells’ spatial and temporal dynamic changes utilizing from multiplex immunohistochemistry to spatial transcriptomic methodologies. Furthermore, the investigation of spatial engagement patterns of T cells with neighbor stromal, other immune, or tumor cells can provide insights into their state of activation and function. Thus, this chapter aimed to unveil the evolving nature of T-cell spatial distribution using multiplex immunohistochemistry, an automated image quantitation analysis applied to investigating colorectal cancer liver metastases. This methodology has proven to be a powerful investigative tool to enable spatial and phenotypic characterization of immune and stromal cells in the tumor immune microenvironment.