Modern Pathology-Driven Strategies in Neoadjuvant Immunotherapy for Head and Neck Squamous Cell Carcinoma: From Residual Tumor Quantification to Spatial and AI-Based Biomarkers

Neoadjuvant strategies in head and neck squamous cell carcinoma (HNSCC) are reshaping therapeutic paradigms by shifting emphasis from anatomical staging toward biology-driven response stratification. The transition from induction chemotherapy to immune checkpoint-based and combination regimens has transformed the perioperative setting into a translational platform that enables interrogation of tumor-immune interactions and clonal selection under therapeutic pressure prior to surgery. In this context, pathological response assessment has emerged as a robust surrogate endpoint, overcoming the limitations of radiologic evaluation, which often fails to capture immune-mediated pseudoprogression and spatially heterogeneous regression. Quantification of residual viable tumor (RVT) provides a reproducible metric of therapeutic efficacy, while characterization of immune-related regression beds, tertiary lymphoid structures, macrophage polarization states, and compartment-specific nodal responses offers mechanistic insight into tumor clearance and resistance evolution. Evidence from phase II trials, single-cell sequencing, spatial transcriptomics, and multiplex immune profiling supports the prognostic relevance of pathology-driven endpoints. Integration of digital pathology and artificial intelligence-assisted image analysis further enhances reproducibility and enables high-resolution mapping of residual disease and immune architecture. Within this modern oncologic framework, the neoadjuvant-treated specimen functions as a dynamic biomarker platform guiding response-adapted surgical strategies and biomarker-driven clinical trial design. This study was designed as a narrative review. A structured literature search was performed using PubMed and major oncology journals to identify relevant studies on pathology-driven response assessment in neoadjuvant-treated head and neck squamous cell carcinoma. The review focused on publications addressing histopathological response criteria, immune microenvironment remodeling, spatial profiling technologies, and computational pathology approaches.