Background: Cutaneous squamous cell carcinoma (CSCC) arising from epidermal keratinocytes is highly curable with surgery. Functional anti-cancer immunity is protective of CSCC and high mortality due to local or systemic dissemination is seen in pts. with immune deficiency. ICI treatment is a logical FDA approved option that result in improved outcomes in affected pts. We report our experience in LACSCC pts. receiving ICI treatment and describe correlation between pt. characteristics, tumor histology and treatment outcome. Methods: Following Institutional Review Board approval, we did a retrospective analysis of LACSCC pts. receiving ICI therapy at the Neag Cancer Center who received at least one dose of ICI between 2018-2023. Analysis includes pt. demographics, relevant comorbidities, medications, and tumor histology and tumor infiltrating lymphocytes (TILs) of tumors reviewed with dermatopathologist. Results: Between 2018-2023, 12 pts. with LACSCC met the criteria for analysis. Median age 77.5 years (yrs.), (range 65-102), 9 males, 3 females, tumors sites - head and neck region 8 pts., torso 2 pts., legs 2 pts. Relevant past medical history included treatment of prostate cancer 3, chronic lymphocytic Leukemia 1, psoriasis 2 (one received anti TNF treatment), and MGUS, Parkinson’s disease and dementia in 1 each. Majority of pts. had significant smoking history (9/12), lymphopenia in 8 out of 12 pts. Tumors were poorly differentiated in 6 out of 12 pts. Brisk TILs was present in 7 and non-brisk TILs in 5 pts. 3 pts. with brisk TILs achieved complete remission (CR), one very good partial response (VGPR), 1 partial response (PR) and 2 not evaluable for response. Out of 5 pts. with non-brisk TILS, one achieved CR, one achieved VGPR, 1 PR, 1 stable disease (SD), and 1 progressive disease (PD) in a pt. who received anti TNF treatment of psoriasis. 9 patients are alive between 1 week and 50 months after initiation of treatment. 3 pts. died, one of PD, one of bacterial sepsis and one of Covid. Conclusions: High risk LACSCC affected males with smoking histories in the majority. Durable responses following ICI treatment occurred irrespective of age, while resistant disease was noted in 1 pt. with previous anti TNF treatment. Brisk TILs predicted high response rate and durable responses although some pts. with non-brisk TILs also showed favorable outcomes. Association with previous cancer and macular degeneration may reflect underlying immune deficiency. Three pts. developed infection within two weeks of ICI treatment (urinary tract infection, wound infection, Covid). More studies will shed light at factors compounding immune deficiency and safety of this treatment in a high-risk population.