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

## TL;DR

This paper reviews how pathology assessments after pre-surgery immunotherapy can better predict treatment success in head and neck cancer.

## Contribution

It highlights novel pathology-driven strategies, including digital tools and immune profiling, to evaluate treatment response in neoadjuvant immunotherapy.

## Key findings

- Pathological response assessment is more reliable than imaging for evaluating treatment effectiveness in head and neck cancer.
- Digital pathology and AI improve the reproducibility and detail of residual disease and immune architecture analysis.
- Residual tumor quantification and immune-related changes provide insights into tumor clearance and resistance mechanisms.

## Abstract

Oral cancer is often treated with surgery, but new strategies are exploring treatments given before surgery to shrink the tumor and stimulate the immune system. In this setting, traditional imaging does not always accurately show how much cancer remains. Careful examination of the removed tissue under the microscope provides more reliable information about treatment effectiveness. This review explains how pathologists can measure the amount of residual cancer cells and recognize immune-related changes within the tumor bed. We also discuss how modern technologies, such as digital pathology and molecular profiling, can improve response evaluation and help guide personalized treatment decisions. By standardizing how treatment response is assessed, clinicians may better identify patients who can safely receive less aggressive therapy and those who need additional treatment. This approach aims to improve survival while reducing unnecessary side effects in patients with oral cancer.

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.