•HD-RT ± LD-RT to separate lesions can be safely delivered for IO refractory patients.•HD-RT + LD-RT safely improved lesion-specific response for IO refractory patients.•LD-RT may be a consideration for large tumors or multiple isocenters.•T- and NK cell infiltration was enhanced in lesions treated with LD-RT. To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer. Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20–70 Gy total; 3–12.5 Gy/f), or HD-RT + LD-RT (0.5–2 Gy/f up to 1–10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response CR/PR or stable disease SD) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response. Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% 16/34 vs. 37% 14/38 in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% 9/34 vs. 13% 5/38 in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P < 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT. HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.