Melanoma patients resistant to RAF/MEK-inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease. New drugs that control tumor growth and favorably modulate the immune environment are therefore needed. We report that the small molecule CX-6258 has potent activity against both RMi sensitive (RMS) and resistant (RMR) melanoma cell lines. Haspin Kinase (HASPIN) was identified as a target of CX-6258. HASPIN inhibition resulted in reduced proliferation, frequent formation of micronuclei (MN), recruitment of cGAS and activation of the cGAS-STING-pathway. In murine models, CX-6258 induced a potent cGAS-dependent type-I-interferon response in tumor cells, increased IFNγ-producing CD8+ T-cells and reduced Treg frequency in vivo. HASPIN was more strongly expressed in malignant compared to healthy tissue and its inhibition by CX-6258 had minimal toxicity in ex vivo expanded human tumor-infiltrating lymphocytes (TILs), proliferating TILs and in vitro differentiated neurons, suggesting a potential therapeutic index for anti-cancer therapy. Furthermore, the activity of CX-6258 was validated in several Ewing sarcoma and multiple myeloma cell lines. Thus, HASPIN inhibition may overcome drug resistance in melanoma, modulate the immune environment and target a vulnerability in different cancer lineages.