INTRODUCTION

Proton therapy is an advanced form of radiation therapy that precisely targets tumors while minimizing damage to surrounding healthy tissues. Its main advantages are derived from its unique physical properties, with the Bragg peak being the most notable. 1 Over the past few decades, the clinical applications of proton therapy have significantly progressed. In 2019, Yuan et al. summarized the application of proton therapy in treating head and neck squamous cell carcinoma (HNSCC), breast cancer (BC), non–small cell lung cancer (NSCLC), hepatocarcinoma (HCC), and prostate cancer. 2 Furthermore, the pediatric, 2 old, 3 and pregnant 4 patients may benefit the most from proton therapy for certain types of cancers.

The tumor immune system plays a crucial role in tumor progression and response to therapy. 5 In this review, we describe the draining lymph nodes, peripheral blood immune cells, immune response of tumor cells, and the tumor immune microenvironment (TIME). (i) Proton therapy reduces radiation exposure to the draining lymph nodes, which are the primary sites for antigen presentation and T cell priming, which in turn better preserves the anti‐tumor immunity of the body. (ii) In peripheral blood immune cells, proton therapy exerts low irradiation toxicity, leading to a more pronounced active immunotherapy response. (iii) Stronger immunogenicity is triggered by proton therapy, which enhances the immune response of tumor cells. (iv) In the TIME, proton therapy builds a complicated immune landscape comprising various immune cells, cytokines, chemokines, and immune checkpoints that interact dynamically with tumor cells. The interaction among these elements can either promote tumor growth or enhance anti‐tumor immunity, highlighting the requirement for further research on the TIME. 6 , 7 , 8 , 9 , 10 Therefore, understanding the evolution of the tumor immune system in response to proton therapy is essential for developing effective treatment strategies and improving patient outcomes.

The combination of proton therapy with immunotherapy and/or chemotherapy has gradually been utilized for the treatment of HNSCC, NSCLC, esophageal carcinoma, lymphoma, and pancreatic cancer. This review comprehensively describes the advantages and disadvantages of combination therapies for various tumor types. However, owing to the lack of sufficient clinical evidence, conducting large‐scale multi‐center prospective clinical trials is a direction for further study.

This review aims to provide an overview of the current understanding of proton therapy, particularly its effects on the tumor immune system, and related therapeutic strategies. In addition, we summarize bulk RNA sequencing for proton therapy, emphasizing the necessity for single‐cell RNA sequencing in future research.