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Resistant tumor cells are difficult for macrophages to clear, prompting investigation of Ganoderma immunomodulatory protein (GMI) as an immunomodulatory adjunct. The study tests whether GMI overcomes Gefitinib and Osimertinib resistance by enhancing macrophage polarization and suppressing the STAT3/CD47 pathway. Using Western blot and RT-qPCR, GMI reduces STAT3 phosphorylation and downstream CD47 expression in parental and resistant cells; restoring STAT3 reverses key apoptotic and CD47 effects.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/ganoderma-microsporum-immunomodulatory-protein-gmi-enhances-phagocytosis-by-suppressing-stat3cd47-signaling-in-egfr-mutant-nsclc-resistant-to-gefitinib-and-osimertinib/407318/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/ganoderma-microsporum-immunomodulatory-protein-gmi-enhances-phagocytosis-by-suppressing-stat3cd47-signaling-in-egfr-mutant-nsclc-resistant-to-gefitinib-and-osimertinib/407318.png","ImageObject",300,407,{"name":92,"@type":93},"Ezra","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is resistance to EGFR-targeted therapy a key problem in NSCLC?","Question",{"text":112,"@type":113},"Although EGFR-TKIs such as gefitinib and erlotinib can initially outperform chemotherapy, most patients develop disease progression after roughly 9–13 months, described as acquired resistance.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What is the proposed role of GMI in overcoming Gefitinib/Osimertinib resistance?",{"text":117,"@type":113},"GMI is proposed to overcome resistance by enhancing macrophage-related clearance mechanisms, including modulating macrophage polarization and reducing tumor-evasive signals.",{"name":119,"@type":110,"acceptedAnswer":120},"How does GMI affect the STAT3/CD47 pathway and macrophage phagocytosis?",{"text":121,"@type":113},"GMI attenuates STAT3 phosphorylation and reduces CD47 transcription and expression; it also increases macrophage phagocytotic activity toward tumor cells, with effects linked to inhibition of the STAT3–CD47 axis.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},407318,1791119250,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},1099514068035,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Ivyspring  \nInternational Publisher  \nJournal of Cancer  \n2026; 17(1): 86-98. doi: 10.7150/jca.124363  \nResearch Paper  \nGanoderma microsporum Immunomodulatory Protein (GMI) Enhances Phagocytosis by Suppressing STAT3/ CD47 Signaling in EGFR-Mutant NSCLC Resistant to Gefitinib and Osimertinib  \nYa-Chu Hsieh1, I-Lun Hsin1, Ling-Yen Chiu1, Yu-Chien Hung1,2,3, Yu-Ting Kang1,4, Hui-Yi Chang1, Ching-Hsiung Lin5􀀍, Jiunn-Liang Ko1,6􀀍, Yu-Fan Liu7,8􀀍  \n1. Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.  \n2. Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung, Taiwan.  \n3. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.  \n4. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.  \n5. Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua City, Taiwan.  \n6. Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan.  \n7. Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan.  \n8. Division of Allergy, Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan.  \n􀀍 Corresponding authors: Jiunn-Liang Ko ([jlko@csmu.edu.tw](jlko@csmu.edu.tw)) Institute of medicine, Chung Shan Medical University, 110, Sec. 1, Chien-Kuo N. Road, Taichung, Taiwan 40201 Tel: +886-4-24730022\\#11694, Ching-Hsiung Lin ([47822@cch.org.tw](47822@cch.org.tw)) or Yu-Fan Liu ([yfliu@csmu.edu.tw](yfliu@csmu.edu.tw)).  \n© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions.  \nReceived: 2025.08.28; Accepted: 2025.11.06; Published: 2026.01.01  \nAbstract  \nTarget therapy is effective for epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC). However, resistance often occurs after treatment for several months. Macrophages have difficulty in devouring resistant cells. Ganoderma immunomodulatory protein (GMI) exhibits anti-tumour and immunomodulatory activities. This study aimed to investigate whether GMI overcomes Osimertinib (Tagrisso) and Gefitinib (Iressa) resistance via enhancing macrophage polarization. GMI attenuated signal transducer and activator of transcription 3 (STAT3) phosphorylation and downstream CD47 expression in parental and resistant cells via Western blot and RT-qPCR. Overexpressed STAT3 restored GMI-induced apoptosis and GMI-reduced transcription of CD47 in HCC827 and H1975 lung cancer cells. Phospho-STAT3 inhibitor (W1131) also reduced the expression of CD47 in NSCLC cells. The interaction between GMI and W1131 was effective in reducing phosphorylated STAT3 and CD47. ImageXpress Pico analysis revealed that GMI enhanced phagocytotic activity of macrophages toward tumour cells with Red CMTPX and Green CMFDA dyes. The results showed that GMI enhanced macrophage phagocytosis of lung cancer cells by inhibiting STAT3 and reducing CD47 expression. In addition, GMI enhanced M1 inhibition of M2 polarization but had no effect on M1 differentiation. This is the first study to demonstrate that GMI enhances macrophage phagocytosis and modulates the STAT3–CD47 axis to overcome EGFR-TKI resistance in NSCLC, highlighting its potential as a novel adjunct immunotherapeutic agent.  \nKeywords: Ganoderma immunomodulatory protein, Epidermal growth factor receptor, Signal transducer and activator of transcription 3, CD47, Phagocytotic, Lung cancer.  \n1. Introduction  \nLung cancer remains the first most prevalent human malignancy and represents a leading cause of cancer-related deaths worldwide in the latest  \nGLOBOCAN estimates [1] . Several phase III clinical trials have established that gefitinib and erl","cbCairca5G7B9sYq","https://ap.wps.com/l/cbCairca5G7B9sYq","pdf",6010209,13,"English","# Introduction\n## Targeted therapy and EGFR-mutant NSCLC resistance\n## Fungal immunomodulatory proteins and GMI background\n## STAT3 signaling as a therapeutic target","[{\"question\":\"Why is resistance to EGFR-targeted therapy a key problem in NSCLC?\",\"answer\":\"Although EGFR-TKIs such as gefitinib and erlotinib can initially outperform chemotherapy, most patients develop disease progression after roughly 9–13 months, described as acquired resistance.\"},{\"question\":\"What is the proposed role of GMI in overcoming Gefitinib/Osimertinib resistance?\",\"answer\":\"GMI is proposed to overcome resistance by enhancing macrophage-related clearance mechanisms, including modulating macrophage polarization and reducing tumor-evasive signals.\"},{\"question\":\"How does GMI affect the STAT3/CD47 pathway and macrophage phagocytosis?\",\"answer\":\"GMI attenuates STAT3 phosphorylation and reduces CD47 transcription and expression; it also increases macrophage phagocytotic activity toward tumor cells, with effects linked to inhibition of the STAT3–CD47 axis.\"}]","Ganoderma microsporum Immunomodulatory Protein (GMI) Enhances Phagocytosis by Suppressing STAT3/CD47 Signaling in EGFR-Mutant NSCLC Resistant to Gefitinib and Osimertinib | PDF",1790573018,33]