Head-and-neck cancers constitute a heterogeneous group of aggressive tumors with high incidence and low survival rates, collectively being the sixth most prevalent cancer type globally. About 90% of head-and-neck cancers are classified as squamous cell carcinomas (HNSCC). The innate and adaptive immune systems, indispensable for anti-cancer immune surveillance, largely define the rates of HNSCC emergence and progression. HNSCC microenvironments harbor multiple cell types that infiltrate the tumors and interact both with tumor cells and among themselves. Gradually, tumor cells learn to manipulate the immune system, either by adapting their own immunogenicity or through the release of immunosuppressive molecules. These interactions continuously evolve and shape the tumor microenvironment, both structurally and functionally, facilitating angiogenesis, proliferation and metastasis. Our understanding of this evolution is directly related to success in the development of advanced therapies. This review focuses on the key mechanisms that rule HNSCC infiltration, featuring particular immune cell types and their roles in the pathogenesis. A close focus on the tumor-immunity interactions will help identify new immunotherapeutic targets in patients with HNSCC.

The current understanding of the effects of radiation is gradually becoming broader. However, it still remains unclear why some patients respond to radiation with a pronounced positive response, while in some cases the disease progresses. This is the motivation for studying the effects of radiation therapy not only on tumor cells, but also on the tumor microenvironment, as well as studying the systemic effects of radiation. In this framework, we review the biological effects of two types of radiotherapy: photon and proton irradiations. Photon therapy is a commonly used type of radiation therapy due to its wide availability and long-term history, with understandable and predictable outcomes. Proton therapy is an emerging technology, already regarded as the method of choice for many cancers in adults and children, both dosimetrically and biologically. This review, written after the analysis of more than 100 relevant literary sources, describes the local effects of photon and proton therapy and shows the mechanisms of tumor cell damage, interaction with tumor microenvironment cells and effects on angiogenesis. After systematic analysis of the literature, we can conclude that proton therapy has potentially favorable toxicological profiles compared to photon irradiation, explained mainly by physical but also biological properties of protons. Despite the fact that radiobiological effects of protons and photons are generally similar, protons inflict reduced damage to healthy tissues surrounding the tumor and hence promote fewer adverse events, not only local, but also systemic.

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