The goal of this prospective, single-arm, phase II trial is to evaluate whether a preoperative regimen combining spatially fractionated radiation therapy (SFRT) with subsequent surgery can improve outcomes in patients with large (≥5 cm) limb/trunk soft tissue sarcoma (STS). Currently, there is a lack of standardized SFRT-based protocols for operable or borderline-resectable large STS, and optimal dose-fractionation schedules, timing to surgery, differential efficacy by resectability status, and the induced systemic immune response remain undefined. Patients will receive 5 fractions of SFRT to the primary tumor, followed by definitive surgery. The main questions are:

• Can this SFRT-first approach increase the 1-year disease-free survival (DFS) compared with historical controls?
• What are the pathologic complete response (pCR) rate, overall survival (OS), and treatment-related safety profile?
• What immune mechanisms are engaged by SFRT, as reflected by dynamic changes in peripheral immune cell subsets and cytokines? Participants will undergo SFRT, then surgery, with serial blood sampling for immune monitoring.

For localized STS, surgery combined with radiotherapy is the standard of care. Preoperative radiotherapy can reduce tumor volume, facilitate resection, and lower recurrence risk. However, two major challenges remain: (1) radioresistance-STS is generally radioresistant, especially in bulky tumors; pivotal studies (e.g., RTOG 0630) report pathologic complete response (pCR) rates below 20% with conventional fractionation; (2) limited local control in unresectable cases-historical data show 5-year local control below 10% for tumors >10 cm treated with definitive radiotherapy alone.

Spatially fractionated radiation therapy (SFRT) delivers high-dose peaks within the tumor while maintaining lower-dose valleys, creating a non-uniform dose distribution that may enhance tumor kill, potentially trigger systemic antitumor immunity, and spare adjacent normal tissues. Recent retrospective data from Mayo Clinic (2024) demonstrated that in advanced, unresectable sarcomas, SFRT followed by conventional external-beam radiotherapy achieved 1-year local control of 82% and symptom relief in 60%, with acceptable toxicity. These promising results support prospective evaluation of SFRT in the preoperative setting for operable or borderline-resectable large STS.

Eligible patients will receive SFRT to the primary tumor in 5 fractions, followed by definitive surgery. The primary endpoint is 1-year disease-free survival (DFS). Secondary endpoints include pCR rate, overall survival (OS), and safety assessed by CTCAE v5.0. Exploratory objectives involve longitudinal monitoring of peripheral blood immune cell subsets (e.g., CD8⁺, CD4⁺, Treg cells) and cytokines (e.g., IFN-γ, TNF-α) to characterize SFRT-induced systemic immune modulation and identify potential biomarkers of response.

Inclusion Criteria:

• Histologically confirmed soft tissue sarcoma of the extremity or trunk, with tumor size ≥5 cm in greatest dimension (by imaging or clinical examination).
• Disease classified as operable or borderline-resectable as determined by the multidisciplinary tumor board.
• Age ≥18 years at the time of consent.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Adequate organ function as defined by:

Absolute neutrophil count ≥1.5 × 10⁹/L; Platelet count ≥100 × 10⁹/L; Hemoglobin ≥9.0 g/dL; Total bilirubin ≤1.5 × upper limit of normal (ULN) (or ≤3 × ULN in patients with Gilbert's syndrome); AST/ALT ≤2.5 × ULN; Creatinine clearance ≥50 mL/min (by Cockcroft-Gault or measured);

• Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment and agree to use effective contraception during the study treatment period and for at least 3 months after the last study procedure. Men with partners of childbearing potential must agree to use effective contraception during the same period.
• Willing and able to provide written informed consent and comply with all study procedures, including scheduled follow-up visits and blood sample collections.

Exclusion Criteria:

• Prior radiotherapy to the same anatomical site that would result in overlap of radiation fields.
• Distant metastases at the time of enrollment (M1 disease).
• Pregnancy or breastfeeding.
• Active second malignancy requiring systemic therapy within the past 3 years, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ.
• Severe, active comorbidities including but not limited to:

Uncontrolled infection requiring intravenous antibiotics; Decompensated heart failure (New York Heart Association Class III or IV); Myocardial infarction or unstable angina within 6 months; Severe chronic obstructive pulmonary disease or other conditions that would preclude safe radiotherapy or surgery.

• Known hypersensitivity to radiation therapy procedures or inability to undergo required imaging (e.g., MRI contrast allergy not manageable with premedication).
• Concurrent participation in another interventional clinical trial with an investigational agent within 30 days prior to enrollment.
• Any condition that, in the opinion of the investigator, would compromise patient safety, interfere with study compliance, or preclude successful completion of the study procedures.