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Background Long-term immunosuppression following organ transplantation is a major risk factor for cutaneous malignancy, one of the leading causes of death among transplant recipients. Immune checkpoint inhibitors (ICIs) have emerged as a pivotal treatment option, inducing remission in advanced cutaneous malignancies including melanoma, squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC). However, the concurrent use of ICIs and immunosuppressants may counteract each other, potentially leading to allograft rejection or treatment failure in organ transplant recipients.Methods We retrospectively collected clinical data from solid organ transplant recipients who received ICIs in 2017-2024 at Inova Schar Cancer Institute.Results We present nine cases of advanced, treatment-resistant cutaneous malignancies following organ transplantation (6 kidney, 2 lung, and 1 combined kidney-lung) treated with ICIs. Clinical characteristics are summarized in table 1. While receiving immunosuppressive regimens comprising various combinations of sirolimus, everolimus, prednisone, cellcept, cyclosporine, tacrolimus, belatacept, and mycophenolate, patients were diagnosed with cutaneous malignancies: 7 SCCs, 1 nasal melanoma, and 1 MCC of the chest. At initial diagnosis, patients presented with stage III or IV disease, often with nodal, lung, or liver metastases, and were refractory to prior treatments including radiation and/or cetuximab.Initiation of PD-1 inhibitors (either pembrolizumab or cemiplimab) resulted in 5 complete responses (CR), 1 partial response (PR), 2 progressive diseases (PD), and 1 case that was not evaluable. Only one patient required a reduction in immunosuppressive dosing during ICI therapy to achieve treatment response. Four patients developed allograft rejections (2 patients in lung, 2 patients in kidney) requiring additional immunosuppression. Of the 5 patients who did not experience organ rejection, outcomes included 3 CRs, 1 PR, and 1 not evaluable. Five patients died, including 4 who had experienced allograft rejection.Conclusions Although ICIs carry a risk of allograft rejection and represent a double-edged sword in organ transplant recipients with cutaneous malignancy, they remain an effective treatment for malignancies resistant to conventional therapy. Careful patient selection and meticulous balancing of ICIs and immunosuppressive therapy, based on the status of both the malignancy and the allograft, are essential to optimize outcomes.Abstract 431 Table 1Clinical characteristics of nine patients diagnosed with cutaneous malignancy after organ transplantation