Background: Immuno-checkpoint inhibitors (ICI) have shown good anti-tumor efficacy and survival benefits in a variety of solid tumors, such lung cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma (HNSCC). ICI have rewritten the guidelines for multiple tumor types. However, there are still a large number of patients who are ineffective or initially effective after use ICI, and subsequently develop ICI resistance. For these patients, how we choose further treatment is currently uncertain clinically. Some studies suggest that even if the treatment of PD - (L) 1 is ineffective or progresses, it can still bring a certain degree of benefit to re-challenge with other target ICI. This study was to evaluate the efficacy and safety of the patients with advanced malignant solid tumors with the regimen of penpulimab. Methods: This is a non-interventive registration study. Eligible participants must be ≥ 18 years old and have proven malignant tumors that are ineffective, fail for immunotherapy and have no other standard treatment. Patients were treated with penpulimab alone or in combination with chemotherapy or anti-angiogenic agents until progression or unacceptable toxicity. The primary endpoint is objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: Form Sep 2021 to Feb 2023, 28 patients (median age 59.5 years, male 71.4%）were recruited, including 9 pts with NSCLC, 5 pts with HNSCC, 4 pts with Nasopharyngeal carcinoma (NPC), 3 pts with esophageal cancer and 7 with other tumor types. Among all, 1 achieved confirmed PR, 21 achieved SD, the ORR was 3.6% (1/28) and the DCR was 78.6% (22/28). The median treatment duration was 9 months. Among the 9 pts with NSCLC, the median treatment duration was 5.6 months and the DCR was 77.8%. Treatment-related adverse events (TRAEs) of grade 3 were observed in 5 (17.9%) of the 28 patients. The most common TRAEs were decreased lymphocyte count (50%, 14/28), anemia (50%, 14/28), hypoalbuminemia (39.3%, 11/28), hyponatremia (25%, 7/28) and hypercholesterolemia (25%, 7/28). Conclusions: Penpulimab-containing regimens for advanced malignant solid tumors that have failed ICI have shown significant efficacy and a favorable safety profile.