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Extremity soft tissue sarcoma (ESTS) is a rare malignant nonepithelial disease, calling for combined modality treatments with surgery to further improve local control rates and long-term survival, especially in patients with multiple local recurrences with or without risk of amputation. In this double-arm, open-label, Phase II clinical trial, we will enroll 30 patients with pathologically confirmed ESTS without nodal involvement or distant metastases. Patients are randomly assigned to the combination treatment group or the radiation monotherapy group. Additionally, tumor and biological samples will be obtained directly before and after neoadjuvant therapy, allowing for studies of immune response and primary drug resistance mechanisms. Clinical Trial Registration:ChiCTR2200060659 (http://www.chictr.org.cn) (ClinicalTrials.gov). Article highlights A combined modality treatments with preoperative radiation therapy and intratumoral immunotherapy for patients with extremity soft tissue sarcomas is proposed. The clinical benefit will rely on the enhancement of immune effects and reduction of related toxicities. Neoadjuvant radiation has a comparable effect on local control and long-term survival with adjuvant radiotherapy after prolonged follow-up. Still, it has significant advantages of less late toxicity and potential benefits from de-escalated surgery, especially for patients with borderline resectable extremity soft tissue sarcomas. Neoadjuvant radiotherapy with hypofractionated regimens has a shorter course of treatment since the total dose is split into larger doses given per fraction compared with standard fractionation. Notably, hypofractionated radiotherapy can facilitate antigen presentation and regulate immune function. Intratumoural injection of antitumor immunomodulator can increase therapeutic effectiveness by mediating agent accumulation in the tumor microenvironment and tumor-draining lymph nodes and may also enhance anti-tumor immunity in combination with radiotherapy. Furthermore, intratumoral immunotherapy is expected to decrease systemic immune exposure while keeping the therapeutic benefits of local control. The nRS group (neoadjuvant radiotherapy alone before surgery) will serve as a control, contrasting the nRIS group (neoadjuvant radiotherapy plus immunotherapy before surgery) in further studies. This study will access radiologic and pathological responses for efficacy evaluation and collect biological samples such as blood draws, stool samples and tumor tissues before and after neoadjuvant therapy for comprehensive mechanistic study. Research team was multidisciplinary and consisted of radiation and medical oncologists, musculoskeletal oncologic surgeons, interventional radiologists, nuclear medicine physicians and specialized pathologists. [ABSTRACT FROM AUTHOR]