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However, low immune infiltration and low antigen presentation in the tumor microenvironment (TME) have led to ineffective ICI immunotherapy in clinical studies. Although intratumoral injection of Toll-like receptor 9 (TLR9) agonists was shown to improve the efficacy of ICIs by increasing the number of tumor-infiltrating lymphocytes (TILs), it has limited effects on metastatic or deep-seated tumors. To overcome this challenge, we developed CpG7909 (a TLR9 agonist) lipoplex using a cationic lipid formulation, which exhibited preferential accumulation in tumors and spleen following systemic administration, Combination immunotherapy with an anti-PD1 antibody and CpG7909 lipoplex significantly promoted the infiltration of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells (&gt;\u2009twofold) into the TME of the CT26 tumor animal model and effectively inhibited both deep-seated colorectal and metastatic lung tumors. Furthermore, the complete response (CR) rate of mice receiving concurrent therapy increased from 0 to 75% compared with that of those receiving anti-PD1 monotherapy. To our knowledge, this study is among the first to evaluate the combination of CpG7909 lipoplexes with anti-PD1 antibodies in the context of cancer immunotherapy. The findings suggest that this approach may convert the TME from an immunologically \u201ccold\u201d to \u201chot\u201d state, thereby enhancing tumor suppression and potentially improving the response rate to ICIs.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-29622-x","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T08:56:14Z","timestamp":1764060974000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Intravenous administration of CpG7909 lipoplex enhances anti-PD1 immunotherapy by modulating the tumor microenvironment and inducing durable tumor regression"],"prefix":"10.1038","volume":"15","author":[{"given":"Chia-Mu","family":"Tu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Hsuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Peng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Ta","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Min","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Ping","family":"She","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Cheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiang-Ching","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Chia","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Wen","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yo-Wen","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Xun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Fu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felice","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen-Kun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Lun","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Hsi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Cheng","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"issue":"5681","key":"29622_CR1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1126\/science.1100369","volume":"305","author":"JN Blattman","year":"2004","unstructured":"Blattman, J. 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