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In this study, the synergistic effects of gene-targeting HIF-1\u03b1 siRNA combined with Toll-Like Receptor 7 agonist on TME remodeling were investigated in a mouse model of colorectal cancer (CRC). A HIF-1\u03b1-specific siRNA duplex was formulated based on the ionic gelation of tripolyphosphate (TPP) with cationic chitosan (CH) as a nanoplex and evaluated in terms of size, charge, polydispersity index and gel retardation assay. MTT assay was conducted to assess the cytotoxicity of the specific siRNA duplex against CT26 cells. Hypoxic condition was generated to evaluate the gene and protein expression levels of HIF-1\u03b1, respectively. CT26 mouse model was established to assess the synergistic effect of silencing HIF-1\u03b1 combined with oxaliplatin (OXA) and imiquimod (IMQ) on tumor growth. The mean diameter of the CH\/siRNA nanoparticles was 243\u2009\u00b1\u20096 nm, as confirmed with Micrograph scanning electron microscope. There were no significant differences observed between the CT26 cells treated with nanoparticles alone and the untreated cells, indicating that these nanoparticles are safe and physiologically biocompatible (<jats:italic>p<\/jats:italic>\u2009\u2265\u20090.05). Triple combination therapy involving HIF-1\u03b1 siRNA, OXA, and IMQ significantly retarded tumor growth and led to elevated levels of cytokines linked to cellular immunity (INF-\u03b3 and IL-12) compared with those in the other groups (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). The positive correlation coefficient (r\u2009=\u20090.68) between tumor size and HIF-1\u03b1 expression levels was statistically significant (<jats:italic>P<\/jats:italic>\u2009=\u20090.003). Compared with those in the control group, the expression levels of the anti-inflammatory cytokines IL-10 and IL-4 significantly decreased (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). In conclusion, our findings suggest that inhibiting HIF-1\u03b1 could serve as a rational strategy to enhance the antitumor response in the TME.<\/jats:p>","DOI":"10.1007\/s00210-024-03658-8","type":"journal-article","created":{"date-parts":[[2024,11,30]],"date-time":"2024-11-30T07:13:53Z","timestamp":1732950833000},"page":"5867-5880","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modulating the tumor microenvironment in a mouse model of colon cancer using a combination of HIF-1\u03b1 inhibitors and Toll-Like Receptor 7 agonists"],"prefix":"10.1007","volume":"398","author":[{"given":"Leila","family":"Rostamizadeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Ramezani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannaneh","family":"Monirinasab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kobra","family":"Rostamizadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2822-5116","authenticated-orcid":false,"given":"Mehdi","family":"Sabzichi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seied Rafi","family":"Bahavarnia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Osouli-Bostanabad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0127-6012","authenticated-orcid":false,"given":"Fatemeh","family":"Ramezani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ommoleila","family":"Molavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,30]]},"reference":[{"key":"3658_CR1","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1007\/s00210-021-02079-1","volume":"394","author":"S Ahmadian","year":"2021","unstructured":"Ahmadian S et al (2021) Sensitization of A-549 lung cancer cells to Cisplatin by Quinacrine-loaded lipidic nanoparticles via suppressing Nrf2 mediated defense mechanism. 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