Beyond the tumor microenvironment: Orchestrating systemic T-cell response for next-generation cancer immunotherapy (Review)

Immune checkpoint blockade therapy has revolutionized cancer treatment, yet its clinical efficacy remains limited to a subset of patients with specific tumor types. The present review provides a comprehensive analysis of T cell-mediated antitumor immunity from both local and systemic perspectives, with particular emphasis on CD8+ T cells as primary effectors. The review discusses how the complex trafficking between the tumor microenvironment (TME), surrounding lymphoid tissues and peripheral circulation creates multiple opportunities for tumors to evade immune surveillance. Within the TME, T-cell exclusion mechanisms, antigen specificity and the spectrum of T-cell exhaustion states, from progenitor exhausted T cells to terminally exhausted T-cell phenotypes, are reviewed. Beyond the local TME, the crucial roles of tumor-draining lymph nodes and tertiary lymphoid structures in maintaining sustainable antitumor immunity, as well as the significance of circulating T cells as both biomarkers and therapeutic targets, are analyzed. This systemic perspective provides insights into the dynamic nature of antitumor immunity and suggests potential strategies for next-generation immunotherapies, including combination approaches targeting multiple immune compartments to achieve optimal therapeutic outcomes.