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Background: The treatment of melanoma, the deadliest form of skin cancer, has greatly benefited from immunotherapy. However, many patients do not show a durable response, which is only partially explained by known resistance mechanisms., Methods: We performed single-cell RNA sequencing of tumor immune infiltrates and matched peripheral blood mononuclear cells of 22 checkpoint inhibitor (CPI)-naive stage III-IV metastatic melanoma patients. After sample collection, the same patients received CPI treatment, and their response was assessed., Findings: CPI responders showed high levels of classical monocytes in peripheral blood, which preferentially transitioned toward CXCL9-expressing macrophages in tumors. Trajectories of tumor-infiltrating CD8 + T cells diverged at the level of effector memory/stem-like T cells, with non-responder cells progressing into a state characterized by cellular stress and apoptosis-related gene expression. Consistently, predicted non-responder-enriched myeloid-T/natural killer cell interactions were primarily immunosuppressive, while responder-enriched interactions were supportive of T cell priming and effector function., Conclusions: Our study illustrates that the tumor immune microenvironment prior to CPI treatment can be indicative of response. In perspective, modulating the myeloid and/or effector cell compartment by altering the described cell interactions and transitions could improve immunotherapy response., Funding: This research was funded by Roche Pharma Research and Early Development., Competing Interests: Declaration of interests R.S., S. Hoves, M.B., T.H., S.D., E.Y., F.L., S. Herter, P.U., A.I., J.S., J.S.-P., T.K.-T., I.G.d.M., and P.C.S. are employed by and hold F. Hoffmann-La Roche Ltd. company stock. P.U. and M.B. disclose ownership of F. Hoffmann-La Roche Ltd. patents. R.D. has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME outside of the submitted work. M.P.L. receives project-specific research support outside of the scope of this work from Roche, Novartis, Molecular Partners, and Oncobit., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)