Immunotherapy in Oral Squamous Cell Carcinoma: A Systematic Review of Resistance Mechanisms and Combination Strategies

Immune-based therapies have become a main focus of research in Head and Neck Squamous Cell Carcinoma (HNSCC)/Oral Squamous Cell Carcinoma (OSCC), with an aim of counteracting tumour immune evasion mechanisms by blockade of immune checkpoint features and boosting anti-tumoural immunity. Following PRISMA (2020) guidelines, this systematic review evaluated findings in PubMed, Scopus, Web of Science, and ClinicalTrials.gov (January 2013-October 2025) databases describing OSCC, HNSCC, or oropharyngeal carcinoma patients treated with immune checkpoint inhibitors or chimeric antigen receptor (CAR)-T modalities. Survival, response rates, immune-related adverse events, and resistance mechanisms were evaluated using Cochrane and ROBINS-I tools. Out of 1,215 retrieved articles, 09 publications were included in the review. PD-1 inhibitors given before surgery, such as camrelizumab and pembrolizumab, either alone or in combination with chemotherapy or VEGFR2 blockade, were well tolerated and resulted in good tumour downstaging. Several randomised trials, especially KEYNOTE-048, demonstrated that survival was extended in those populations with high PD-L1 expression levels. Initial CAR-T and vaccine-based immunotherapies also triggered immune activation, which are very promising results. In general, immunotherapy shows a favourable efficacy and safety profile in OSCC. However, other large-scale Phase III trials focused on OSCC that will address further personalisation of these treatment approaches are warranted. Where available, OSCC-specific data were used for subgroup analysis of results; nevertheless, a certain proportion of the evidence came from mixed HNSCC/OPC populations.