Spatiotemporal CD8

The clinical success of immune checkpoint inhibitors (ICI) has shifted the paradigm of cancer treatment, yet the fundamental mechanisms governing the long-term sustainability of antitumor T-cell responses remain elusive. Emerging evidence suggests that the efficacy of ICI depends not only on the reinvigoration of pre-existing tumor-infiltrating lymphocytes but also on the continuous mobilization and replacement of T-cell clones from systemic reservoirs. In this review, we propose a "spatiotemporal ecosystem model" of the antitumor T-cell response. We first delineate the spatial dynamics of T-cell clones, where tumor-reactive progenitors primed in the tumor-draining lymph nodes (dLN) circulate through the peripheral blood to replenish the tumor microenvironment (TME). We highlight that TCR avidity emerges as a key determinant of clonal fate; while high-avidity clones provide potent early cytotoxicity, their susceptibility to accelerated terminal exhaustion eventually creates an available niche that allows for the subsequent expansion of intermediate-avidity successor clones. Furthermore, we discuss how single-cell multi-omics integration (transcriptome, TCR repertoire, and epigenome) reveals that clonal fate is functionally encoded in the molecular and metabolic poise of T cells prior to their expansion. Finally, we discuss the potential of monitoring these clonal dynamics through liquid biopsy as a non-invasive window into the resilience of the immune ecosystem, distinguishing responders with sustainable, polyclonal mobilization from non-responders with frustrated, oligoclonal responses. By integrating clonal evolution, metabolic fitness, and inter-organ crosstalk, this ecosystem perspective offers a comprehensive framework for predicting therapeutic outcomes and developing next-generation precision immunotherapies.