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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background and Aim: Cordycepin (CDC), an adenosine (ADO) analog from Cordyceps mushrooms, exhibits potent anti-tumor and immunomodulatory activities. However, the precise mechanisms governing its effects on macrophage plasticity remain poorly understood. This study aimed to isolate CDC from a high-yielding Cordyceps cultivar, validate its systemic anti-tumor efficacy, and elucidate the mechanobiological cues regulating CDC-driven macrophage functions under varying cell-density states. Experimental Procedure: CDC (&gt;98% purity) was isolated and structurally characterized via nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). Primary bone marrow-derived macrophages and RAW264.7 cells, cultured under sparse (~30%) or confluent (100%) conditions, were treated with CDC or ADO. We evaluated cell viability, pro-inflammatory cytokine expression, and Nuclear Factor kappa B (NF-\u03baB) p65 signaling, phagocytosis, and migration. The therapeutic potential of CDC-primed macrophages was assessed via in vitro melanoma co-culture and in vivo intratumoral adoptive transfer in B16F10 tumor-bearing mice. Key Results: Systemic administration of CDC significantly inhibited melanoma growth in vivo, promoting apoptosis, enhancing macrophage infiltration. We discovered that CDC regulates macrophage functions via a density-dependent \u201cswitch\u201d: while CDC induced cytotoxicity in sparse cultures, it significantly augmented M1-like cytokine production in confluent states without compromising viability. This density-dependent activation was mediated by the A2A adenosine receptor (A2AR), triggering the Akt\u2013NF-\u03baB p65 signaling axis. Furthermore, CDC upregulated migration- and phagocytosis-associated genes, enhancing tumor cell clearance. Notably, intratumoral injection of CDC-primed macrophages markedly reduced tumor volume and size in vivo. Conclusions and Implications: CDC modulates macrophage activation through a unique mechanobiological switch. Under high-density conditions\u2014mimicking the dense tumor microenvironment\u2014CDC enhances A2AR-mediated NF-\u03baB activation, boosting macrophage activation, recruitment, and phagocytosis to facilitate tumor regression. These findings establish CDC as a context-dependent immunomodulator capable of reprogramming macrophages toward a tumoricidal phenotype.<\/jats:p>","DOI":"10.31083\/fbl52067","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:29:27Z","timestamp":1777454967000},"source":"Crossref","is-referenced-by-count":0,"title":["Context-Dependent Modulation of Macrophage Plasticity by Cordycepin Drives Tumor Regression in Melanoma"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2999-8790","authenticated-orcid":true,"given":"Jihae","family":"Lim","sequence":"first","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5383-7598","authenticated-orcid":true,"given":"Donglan","family":"Piao","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3225-9848","authenticated-orcid":true,"given":"Jio","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2116-6966","authenticated-orcid":true,"given":"Suh Jin","family":"Yoon","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Republic of Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, 03760 Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0505-1196","authenticated-orcid":true,"given":"Hyun Ji","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Republic of Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, 03760 Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8851-0720","authenticated-orcid":true,"given":"Isoo","family":"Youn","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1950-2348","authenticated-orcid":true,"given":"Eun Kyoung","family":"Seo","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8508-3666","authenticated-orcid":true,"given":"Eun Sook","family":"Hwang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Republic of Korea"},{"name":"Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, 03760 Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Khan MA, Tania M. 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