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Background/Objectives: Proton therapy has emerged as an advanced radiotherapy modality due to its unique physical dose distribution and its distinct radiobiological properties. The finite range of protons in tissue enables highly conformal dose delivery with minimal exit dose, significantly reducing irradiation of surrounding normal tissues compared to photon-based radiotherapy. Beyond these physical advantages, proton beams exhibit a spatially varying linear energy transfer that increases toward the distal edge of the spread-out Bragg peak, leading to clustered and complex DNA damage that is more difficult for cancer cells to repair. Methods: This review integrates experimental, computational, and clinical evidence to examine how proton-induced DNA damage, relative biological effectiveness, oxygen effects, and non-targeted responses contribute to tumor control and normal tissue sparing. Results: Comparative analyses with photon intensity-modulated radiotherapy demonstrate consistent reductions in acute and late toxicities across multiple tumor sites, particularly in pediatric patients and in tumors located near critical organs. The review also discusses emerging technologies, including pencil beam scanning, image-guided and adaptive proton therapy, compact accelerator systems, and ultra-high dose rate FLASH proton therapy, which collectively aim to enhance treatment precision, biological effectiveness, and accessibility. Conclusions: Together, these developments support proton therapy as a rapidly evolving modality with significant potential to improve therapeutic outcomes in modern oncology.
