The immunological window in oral cancer: Integrating the progenitor exhausted T cells/terminally exhausted T cells axis and tumor-draining lymph nodes into oral and maxillofacial surgical practice

Objective Perioperative immune checkpoint inhibition has changed the conceptual framework of treating resectable locally advanced head and neck squamous cell carcinoma. This review aims to provide oral and maxillofacial surgeons with a practical immunological framework for interpreting perioperative immune checkpoint inhibition in oral cancer. Methods This narrative review summarizes and interprets recent clinical trials, guidelines, and translational studies relevant to perioperative pembrolizumab, PD-1 signaling, T-cell exhaustion, tumor-draining lymph nodes, tertiary lymphoid structures, pathological response, immune-related adverse events, and molecular residual disease. Results Perioperative pembrolizumab has shifted immune checkpoint inhibition from a treatment for recurrent or metastatic disease to a curative-intent strategy integrated with surgery. PD-1 signaling should be understood as a rheostat that regulates T-cell receptor and CD28 signaling rather than as a simple inhibitory brake. Durable responses to immune checkpoint inhibition are hypothesized to depend on the preservation and functional availability of the progenitor exhausted T-cell reservoir and its capacity to supply tumor-reactive progeny to the tumor microenvironment. Tumor-draining lymph nodes and tertiary lymphoid structures are therefore not only anatomical or pathological entities but also coordinated, multicellular immunological niches involving CD8-positive T-cell differentiation, CD4-positive helper subsets, B cells, and antigen-presenting cells relevant to treatment response. Surgical specimens after preoperative treatment should be interpreted as sources of pathological, spatial, immune, and molecular information. Conclusions Oral and maxillofacial surgeons should integrate tumor immunology into perioperative decision-making, specimen handling, adverse-event management, and translational research. This immune-aware framework may improve the interpretation of surgical treatment in the era of perioperative immunotherapy.