{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:43:50Z","timestamp":1785437030601,"version":"3.56.0"},"reference-count":98,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["U54CA096297"],"award-info":[{"award-number":["U54CA096297"]}]},{"name":"National Cancer Institute","award":["U54CA096300"],"award-info":[{"award-number":["U54CA096300"]}]},{"award":["U54CA096297"],"award-info":[{"award-number":["U54CA096297"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U54CA096300"],"award-info":[{"award-number":["U54CA096300"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM149367"],"award-info":[{"award-number":["P30GM149367"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P30GM149367"],"award-info":[{"award-number":["P30GM149367"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin malignancy characterized by high mortality and a rising incidence. Although immune checkpoint inhibitors have significantly improved patient outcomes, many patients exhibit primary or acquired resistance, frequently in the setting of an immunosuppressive tumor microenvironment (TME) enriched for myeloid populations. This review synthesizes current evidence and proposes a testable model in which nicotinic acetylcholine receptor (nAChR) signaling may intersect with tumor-associated macrophage (TAM) biology to reinforce immune exclusion in MCC. Direct MCC-specific evidence currently supports nAChR-subunit expression in tumor tissues and the association of CD163+\/CD14+\/S100A8+ myeloid populations with resistance to PD-1 pathway blockade; however, functional nAChR signaling in MCC tumor cells, TAMs, or dendritic cells has not yet been demonstrated. We therefore distinguish established MCC observations from mechanistic hypotheses extrapolated from macrophage biology, cholinergic anti-inflammatory signaling, and other cancer models. Within this framework, \u03b17-nAChR signaling on TAMs may activate the cholinergic anti-inflammatory pathway and favor suppressive myeloid states, whereas \u03b13- and \u03b15-containing receptors detected in MCC tumor cells may represent tumor-cell-associated candidates for future mechanistic testing. By integrating evidence on TAM plasticity, spatial immune exclusion, and cholinergic signaling, we propose that the nAChR\u2013macrophage axis is a rational but unproven therapeutic hypothesis that warrants systematic validation in MCC models.<\/jats:p>","DOI":"10.3390\/ijms27146331","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:12:38Z","timestamp":1784257958000},"page":"6331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Nicotinic Acetylcholine Receptor\u2013Macrophage Axis in Merkel Cell Carcinoma: Evidence, Limitations, and Therapeutic Hypotheses"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4757-0905","authenticated-orcid":false,"given":"Jeymily","family":"Ares-Estrada","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Garc\u00eda-Qui\u00f1ones","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Puerto Rico, San Juan, PR 00925, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 A.","family":"Lasalde-Dominicci","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Puerto Rico, San Juan, PR 00925, USA"},{"name":"Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR 00936, USA"},{"name":"University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leomar Y.","family":"Ballester","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3398-0573","authenticated-orcid":false,"given":"Phyu P.","family":"Aung","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2146-1071","authenticated-orcid":false,"given":"Manuel","family":"Delgado-V\u00e9lez","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, San Juan, PR 00936, USA"},{"name":"Molecular Sciences Research Center, University of Puerto Rico, San Juan, PR 00936, USA"},{"name":"University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00936, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"vii81","DOI":"10.1093\/annonc\/mdq366","article-title":"Merkel Cell Carcinoma","volume":"21","author":"Becker","year":"2010","journal-title":"Ann. 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