Background: The development of anticancer therapy tends to focusing on pan-cancer analysis, targeted therapy and immunotherapy with the advance of molecular and tumor microenvironment. Radiotherapy produces an immunomodulatory effect that may act synergistically with PD-1/PD-L1 inhibitor in multiple malignancies. Previous phase II trial showed HFRT/SBRT combined with PD-1 inhibitor and GM-CSF (PRaG regimen) has obtained promising results(Yuehong Kong et al. ASTRO 2021). RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC). Preclinical studies indicated that ADC elicit immunogenic cell death and selectively radiosensitize to tumours. RC48-ADC combined with HFRT, PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 (PRaG3.0 regimen) could further improve the synergistic antitumor effects, this precise combination therapy paradigm provides an exploratory path for the treatment of pan-cancer. An exploratory phase II, open-label, multi-centre, single-arm study was conducted to evaluate the initial clinical efficacy and safety of PRaG3.0 regimen for treatment of HER2-expressing advanced solid tumors. Methods: Participants with advanced, confirmed HER2-expressing(IHC3+, 2+ or 1+) solid tumors that had progressed after the standard of care or intolerance were enrolled. In the cycle, those received RC48-ADC(2.0 mg/kg d1, every 3 weeks), then HFRT (2-3 doses of 5-8Gy) was delivered for one metastatic lesion every other day, followed by GM-CSF(200 μg d3-7), sequential IL-2(2million IU d8-12), and PD-1/PD-L1 inhibitor was dosing within one week after completion of HFRT. After RC48-ADC combined with PD-1/PD-L1 inhibitor sequential GM-CSF and IL-2 for at least 6 cycles, then maintenance with PD-1/PD-L1 inhibitor was administered until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). This trial is registered with ClinicalTrials.gov, number NCT05115500. Results: With the cutoff date of 11 February 2022, a total of 8 patients were enrolled. Among 6 patients who had at least one tumor assessment, involved gastric cancer(3/6), breast cancer(1/6), cervical cancer(1/6), pancreatic cancer(1/6). The ORR was 66.7% (4/6) and disease control rate (DCR) was 83.3%(5/6). One cervical cancer and one pancreatic cancer achieved complete remission. The most common treatment-related adverse events (TRAEs) were alopecia (37.5%), fatigue (25%) and hepatic damage(12.5%). No Grade 3 and higher adverse events occurred. Conclusions: The PRaG3.0 regimen manifested manageable safety profile and encouraging efficacy. So PRaG3.0 regimen is considered as a promising salvage treatment for patients with HER2-expressing advanced solid tumors. And the conclusion should be validated in more patients subsequently. Clinical trial information: NCT05115500.