e21529 Background: Cutaneous squamous cell carcinoma (cSCC) with high-risk features is primarily treated with radiations or surgically. However, locally advanced (LA) or metastatic cSCC (mcSCC) may not be managed surgically and require systemic therapy. In this systematic review, we will assess the efficacy of immune checkpoint inhibitors (ICIs) in patients with resectable, LA, or mcSCC. Methods: A literature search was performed on PubMed, Embase, and clinicaltrials.gov with keywords, “cutaneous squamous cell carcinoma” and “immune checkpoint inhibitor” from the inception of data till 12/31/22. After screening of 883 articles, 8 clinical trials (N = 513) were included. Results: In 8 clinical trials (N = 513), 205 patients had LA cSCC, 99 patients had resectable cSCC, and 209 patients had mcSCC. 81 patients were newly diagnosed while 432 patients were relapsed/refractory (RR). Cemiplimab was used to treat 262 patients, pembrolizumab for 227 patients, and nivolumab for 24 patients. In 2 clinical trials (N = 142) on RR LA cSCC, complete response (CR), partial response (PR), overall response (OR), and progressive disease (PD) were 13-17%, 31-33%, 44-50%, and 12-17%, respectively, in patients treated with ICIs. In 3 clinical trials (N = 175) on RR mcSCC, CR, PR, OR, and PD were 7-18%, 25-41%, 36-64%, and 16-26%, respectively. In two clinical trials (N = 81) on ND cSCC patients, CR, PR, OR, and PD were 0-7%, 35-58%, 42-58%, and 32-20%, respectively. In 2 clinical trials (N = 99) on resectable cSCC, pathological CR, pathological major response, and PD were 51-75%, 13-20%, and 10%, respectively, in patients treated with ICIs. Table. Conclusions: ICIs including cemiplimab, pembrolizumab, and nivolumab were effective in the treatment of resectable, LA, and mcSCC. ICIs were effective in the treatment of both R/R and treatment naïve mcSCC. However, no results were available for randomized clinical trials and large-scale randomized studies are needed to confirm these results. [Table: see text]