CD8⁺ T Cell infiltration and spatial organization in cancer: mechanisms, barriers, and therapeutic strategies

Abstract The infiltration of tumors by CD8⁺ T lymphocytes is a critical determinant of antitumor immunity and response to immunotherapy. However, the presence of tumor-specific CD8⁺ T cells does not necessarily translate into effective tumor control, as multiple biological barriers can prevent their recruitment, spatial distribution, persistence, and functional activity. This review provides a comprehensive overview of the multistep mechanisms regulating CD8⁺ T-cell infiltration, from immune priming and systemic trafficking to vascular entry, intratumoral migration, and tissue residency. We discuss how alterations in chemokine networks, dysfunctional tumor vasculature, extracellular matrix remodeling, stromal barriers, and immunosuppressive signals collectively drive immune exclusion and resistance to therapy. Unlike previous reviews that have focused on individual aspects of T-cell trafficking, tumor immune contexture, or immune exclusion, we integrate these interconnected mechanisms as successive biological checkpoints and link them to therapeutic strategies aimed at overcoming specific barriers. These include restoration of antigen presentation and dendritic cell function, reprogramming of chemokine pathways, vascular normalization, stromal remodeling, innate immune activation, and induction of tertiary lymphoid structures. This integrated framework highlights why increasing CD8⁺ T-cell infiltration alone may be insufficient and supports the development of rational, sequential, and spatially guided combination strategies. Advances in spatial transcriptomics, single-cell technologies, and multiplex imaging are expected to enable personalized identification of dominant immune barriers and rational design of combination therapies. Ultimately, the goal is shifting from simply activating T cells toward engineering tumor ecosystems that support sustained CD8⁺ T-cell infiltration, organization, and effector function.