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It features high mutational burden and intense lymphocytic infiltration, supporting the use of immunotherapies, especially inhibitors of the programmed cell death protein 1 (PD-1) checkpoint. Despite advances with anti-PD-1 therapies, such as nivolumab and pembrolizumab, many patients still experience resistance. This result highlights additional immunosuppressive mechanisms within the tumor microenvironment (TME) that limit T-lymphocyte-mediated responses. Objectives: The aim was to discuss the immunologic and metabolic bases of PD-1- and CD73-mediated pathways and evidence that CD73 inhibition can boost PD-1 inhibitor efficacy by acting on convergent immunosuppressive pathways. Methods: We conducted a narrative literature review focusing on tumor immunosuppression, purinergic signaling and checkpoint inhibitor-based immunotherapy. Results: The purinergic pathway, mediated by the ectonucleotidase CD73, is a critical regulator of tumor immunosuppression. CD73 converts extracellular adenosine monophosphate (AMP) into adenosine. This adenosine accumulates in the hypoxic and inflamed TME, exerting immunosuppressive effects. Adenosine acts as a \u201cmetabolic brake,\u201d inhibiting proliferation, cytokine production, and cytotoxic activity of CD8+ T lymphocytes and natural killer (NK) cells. It also promotes the expansion of regulatory T cells (Tregs) and tumor progression. This axis may limit responses to PD-1 blockade, suggesting that complementary pathways are active. Conclusions: Integration of PD-1 and CD73 pathways suggests that CD73 inhibition may enhance PD-1 blockade by targeting convergent immunosuppressive mechanisms. This supports the exploration of combination strategies to broaden the benefits of immunotherapy in CM.<\/jats:p>","DOI":"10.3390\/ph19060913","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:57:17Z","timestamp":1781161037000},"page":"913","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immunosuppressive Pathways in Cutaneous Melanoma: Functional Integration Between PD-1 and CD73 and Therapeutic Implications"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1393-1791","authenticated-orcid":false,"given":"Rayana Vilela","family":"Bertolucci","sequence":"first","affiliation":[{"name":"Medical School, Federal University of Fronteira Sul, Campus Chapec\u00f3, Chapec\u00f3 89815-899, Santa Catarina, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9986-3118","authenticated-orcid":false,"given":"Bruna","family":"Klein","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Campus Chapec\u00f3, Chapec\u00f3 89815-899, Santa Catarina, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5637-6154","authenticated-orcid":false,"given":"Camilla Casarin","family":"Pase","sequence":"additional","affiliation":[{"name":"Medical School, Federal University of Fronteira Sul, Campus Chapec\u00f3, Chapec\u00f3 89815-899, Santa Catarina, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4286-5083","authenticated-orcid":false,"given":"Vit\u00f3ria Capelli","family":"de Melo","sequence":"additional","affiliation":[{"name":"Medical School, Federal University of Fronteira Sul, Campus Chapec\u00f3, Chapec\u00f3 89815-899, Santa Catarina, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarete Dulce","family":"Bagatini","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Campus Chapec\u00f3, Chapec\u00f3 89815-899, Santa Catarina, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Caraviello, C., Nazzaro, G., Tavoletti, G., Boggio, F., Denaro, N., Murgia, G., Passoni, E., Benzecry Mancin, V., and Marzano, A.V. 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