Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel
Identifieur interne : 000032 ( Pmc/Checkpoint ); précédent : 000031; suivant : 000033Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel
Auteurs : Xiaomeng Dai [République populaire de Chine] ; Jingshu Meng [République populaire de Chine] ; Suke Deng [République populaire de Chine] ; Lingling Zhang [République populaire de Chine] ; Chao Wan [République populaire de Chine] ; Lisen Lu [République populaire de Chine] ; Jing Huang [République populaire de Chine] ; Yan Hu [République populaire de Chine] ; Zhanjie Zhang [République populaire de Chine] ; Yan Li [République populaire de Chine] ; Jonathan F. Lovell [États-Unis] ; Gang Wu [République populaire de Chine] ; Kunyu Yang [République populaire de Chine] ; Honglin Jin [République populaire de Chine]Source :
- Theranostics [ 1838-7640 ] ; 2020.
Abstract
Simultaneously targeted treatment of tumor cells and their surrounding growth-supporting immune cells is a promising strategy to reshape immunosuppressive tumor microenvironment (TME) and potentiate host innate and adaptive antitumor immune responses.
Url:
DOI: 10.7150/thno.42385
PubMed: 32194854
PubMed Central: 7053188
Affiliations:
- République populaire de Chine, États-Unis
- Hubei, État de New York
- Buffalo (New York), Wuhan
- Université d'État de New York à Buffalo
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CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel</title><author><name sortKey="Dai, Xiaomeng" sort="Dai, Xiaomeng" uniqKey="Dai X" first="Xiaomeng" last="Dai">Xiaomeng Dai</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Meng, Jingshu" sort="Meng, Jingshu" uniqKey="Meng J" first="Jingshu" last="Meng">Jingshu Meng</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Deng, Suke" sort="Deng, Suke" uniqKey="Deng S" first="Suke" last="Deng">Suke Deng</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Zhang, Lingling" sort="Zhang, Lingling" uniqKey="Zhang L" first="Lingling" last="Zhang">Lingling Zhang</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Wan, Chao" sort="Wan, Chao" uniqKey="Wan C" first="Chao" last="Wan">Chao Wan</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Lu, Lisen" sort="Lu, Lisen" uniqKey="Lu L" first="Lisen" last="Lu">Lisen Lu</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Huang, Jing" sort="Huang, Jing" uniqKey="Huang J" first="Jing" last="Huang">Jing Huang</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Hu, Yan" sort="Hu, Yan" uniqKey="Hu Y" first="Yan" last="Hu">Yan Hu</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Zhang, Zhanjie" sort="Zhang, Zhanjie" uniqKey="Zhang Z" first="Zhanjie" last="Zhang">Zhanjie Zhang</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Li, Yan" sort="Li, Yan" uniqKey="Li Y" first="Yan" last="Li">Yan Li</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Lovell, Jonathan F" sort="Lovell, Jonathan F" uniqKey="Lovell J" first="Jonathan F." last="Lovell">Jonathan F. Lovell</name><affiliation wicri:level="4"><nlm:aff id="A2">Department of Chemical and Biological Engineering, University at Buffalo, State University of New York. Buffalo, New York 14260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemical and Biological Engineering, University at Buffalo, State University of New York. Buffalo, New York 14260</wicri:regionArea><orgName type="university">Université d'État de New York à Buffalo</orgName><placeName><settlement type="city">Buffalo (New York)</settlement><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Wu, Gang" sort="Wu, Gang" uniqKey="Wu G" first="Gang" last="Wu">Gang Wu</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Yang, Kunyu" sort="Yang, Kunyu" uniqKey="Yang K" first="Kunyu" last="Yang">Kunyu Yang</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Jin, Honglin" sort="Jin, Honglin" uniqKey="Jin H" first="Honglin" last="Jin">Honglin Jin</name><affiliation wicri:level="1"><nlm:aff id="A1">Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author></analytic><series><title level="j">Theranostics</title><idno type="eISSN">1838-7640</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Simultaneously targeted treatment of tumor cells and their surrounding growth-supporting immune cells is a promising strategy to reshape immunosuppressive tumor microenvironment (TME) and potentiate host innate and adaptive antitumor immune responses.</p><p><bold>Methods</bold>: We designed a series of melittin-(RADA)<sub>n</sub> hybrid peptide sequences with varying self-assembling motifs of RADA and screened out a melittin-(RADA)<sub>6</sub> peptide that has an optimal gel-formation ability and <italic>in vitro</italic> antitumor activity.</p><p><bold>Results</bold>: The formed melittin-(RADA)<sub>6</sub> (MR<sub>52</sub>) hydrogel scaffold could be loaded with a specific Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CAMKII) inhibitor, KN93, originally found to have both direct tumoricidal activity and macrophages-reprogramming ability, for potent immunotherapy against melanoma and hepatoma ascites in mice models. Our MR<sub>52</sub> hydrogel has an interweaving nanofiber-like structure, possesses direct antitumor and controlled drug release properties<italic>,</italic> and promotes the enhanced intracellular uptake of loaded cargo. Compared to free KN93, the MR<sub>52</sub>-KN93 hydrogel (MRK) improved the killing effects and levels of immunogenic cell death (ICD) on tumor cells significantly. Due to the dual role of KN93, the injection of the MRK hydrogel retarded the growth of subcutaneous melanoma tumors dramatically and resulted in a high number of mature dendritic cells of draining lymph nodes, significantly enhancing the portion of cytotoxic T cells and reduced number of M2-like tumor-associated macrophages (TAMs) in tumors. Using a mouse model of malignant ascites (MAs), where traditional therapy was ineffective, we demonstrated that the MRK hydrogel treatment offered a significantly prolonged survival compared to controls. Following treatment with the MRK hydrogel, macrophages had elevated programmed cell death protein ligand-1 (PD-L1) expression, promising follow-up combined anti-PD-1 therapy that confers a cure rate of approximately 30% against MAs in mice models.</p><p><bold>Conclusion</bold>: Thus, the MRK hydrogel may serve as a prospective platform for antitumor applications.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Holzel, M" uniqKey="Holzel M">M Holzel</name></author><author><name sortKey="Bovier, A" uniqKey="Bovier A">A Bovier</name></author><author><name sortKey="Tuting, T" uniqKey="Tuting T">T Tuting</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zou, W" uniqKey="Zou W">W Zou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nagarsheth, N" uniqKey="Nagarsheth N">N Nagarsheth</name></author><author><name sortKey="Wicha, Ms" uniqKey="Wicha M">MS 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Theranostics</journal-id><journal-id journal-id-type="iso-abbrev">Theranostics</journal-id><journal-id journal-id-type="publisher-id">thno</journal-id><journal-title-group><journal-title>Theranostics</journal-title></journal-title-group><issn pub-type="epub">1838-7640</issn><publisher><publisher-name>Ivyspring International Publisher</publisher-name><publisher-loc>Sydney</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32194854</article-id><article-id pub-id-type="pmc">7053188</article-id><article-id pub-id-type="doi">10.7150/thno.42385</article-id><article-id pub-id-type="publisher-id">thnov10p3049</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>Targeting CAMKII to reprogram tumor-associated macrophages and inhibit tumor cells for cancer immunotherapy with an injectable hybrid peptide hydrogel</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Dai</surname><given-names>Xiaomeng</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Meng</surname><given-names>Jingshu</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Deng</surname><given-names>Suke</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FNA_star">*</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Lingling</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wan</surname><given-names>Chao</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lu</surname><given-names>Lisen</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Jing</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Yan</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Zhanjie</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Yan</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lovell</surname><given-names>Jonathan F.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Gang</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Kunyu</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib><contrib contrib-type="author"><name><surname>Jin</surname><given-names>Honglin</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib></contrib-group><aff id="A1"><label>1</label>Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China</aff><aff id="A2"><label>2</label>Department of Chemical and Biological Engineering, University at Buffalo, State University of New York. Buffalo, New York 14260, USA</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Fax: +86-27-65650733; Tel: +86-27-85873100. Email: Kunyu Yang, <email>yangkunyu@medmail.com.cn</email>; Honglin Jin, <email>jin@hust.edu.cn</email></corresp><fn fn-type="equal" id="FNA_star"><p><sup>*</sup> These authors contributed equally to this work.</p></fn><fn fn-type="COI-statement"><p>Competing Interests: The authors have declared that no competing interest exists.</p></fn></author-notes><pub-date pub-type="collection"><year>2020</year></pub-date><pub-date pub-type="epub"><day>10</day><month>2</month><year>2020</year></pub-date><volume>10</volume><issue>7</issue><fpage>3049</fpage><lpage>3063</lpage><history><date date-type="received"><day>22</day><month>11</month><year>2019</year></date><date date-type="accepted"><day>23</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>© The author(s)</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>). See <ext-link ext-link-type="uri" xlink:href="http://ivyspring.com/terms">http://ivyspring.com/terms</ext-link> for full terms and conditions.</license-p></license></permissions><abstract><p>Simultaneously targeted treatment of tumor cells and their surrounding growth-supporting immune cells is a promising strategy to reshape immunosuppressive tumor microenvironment (TME) and potentiate host innate and adaptive antitumor immune responses.</p><p><bold>Methods</bold>: We designed a series of melittin-(RADA)<sub>n</sub> hybrid peptide sequences with varying self-assembling motifs of RADA and screened out a melittin-(RADA)<sub>6</sub> peptide that has an optimal gel-formation ability and <italic>in vitro</italic> antitumor activity.</p><p><bold>Results</bold>: The formed melittin-(RADA)<sub>6</sub> (MR<sub>52</sub>) hydrogel scaffold could be loaded with a specific Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CAMKII) inhibitor, KN93, originally found to have both direct tumoricidal activity and macrophages-reprogramming ability, for potent immunotherapy against melanoma and hepatoma ascites in mice models. Our MR<sub>52</sub> hydrogel has an interweaving nanofiber-like structure, possesses direct antitumor and controlled drug release properties<italic>,</italic> and promotes the enhanced intracellular uptake of loaded cargo. Compared to free KN93, the MR<sub>52</sub>-KN93 hydrogel (MRK) improved the killing effects and levels of immunogenic cell death (ICD) on tumor cells significantly. Due to the dual role of KN93, the injection of the MRK hydrogel retarded the growth of subcutaneous melanoma tumors dramatically and resulted in a high number of mature dendritic cells of draining lymph nodes, significantly enhancing the portion of cytotoxic T cells and reduced number of M2-like tumor-associated macrophages (TAMs) in tumors. Using a mouse model of malignant ascites (MAs), where traditional therapy was ineffective, we demonstrated that the MRK hydrogel treatment offered a significantly prolonged survival compared to controls. Following treatment with the MRK hydrogel, macrophages had elevated programmed cell death protein ligand-1 (PD-L1) expression, promising follow-up combined anti-PD-1 therapy that confers a cure rate of approximately 30% against MAs in mice models.</p><p><bold>Conclusion</bold>: Thus, the MRK hydrogel may serve as a prospective platform for antitumor applications.</p></abstract><kwd-group><kwd>Hydrogel</kwd><kwd>cancer immunotherapy</kwd><kwd>tumor-associated macrophages</kwd><kwd>anti-PD-1</kwd><kwd>CAMKII</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold> Synthesis, characterization, and <italic>in vitro</italic> antitumor effects of the MRK hydrogel. (A)</bold> Photographs of MR<sub>52</sub> hydrogels or MR<sub>52</sub> hydrogels loaded with various agents. <bold>(B)</bold> The representative TEM image of the MRK hydrogel. Scale bar, 200 nm. <bold>(C)</bold> Comparison of the release rate of Cy5 from the MR<sub>52</sub>-Cy5 hydrogel in the presence or absence of proteinase K. <bold>(D)</bold> Comparison of the MR<sub>52</sub> hydrogel release rate in the presence or absence of proteinase K. <bold>(E)</bold> The NIR fluorescence imaging analysis of the distribution of the MR<sub>52</sub>-Cy5 hydrogel and free Cy5 <italic>in vivo</italic>. The subcutaneous implantation was performed at the indicated time points. <bold>(F)</bold> Quantitative data of the NIR fluorescence imaging results, Data are presented as the mean ± SEM (n = 3). <bold>(G)</bold> Cell viability measurement using the CCK-8 assay. <bold>(H, I)</bold> Clone formation assay (left panel: representative images of cell clones treated with PBS, KN93, and MR<sub>52</sub>, or MRK hydrogel; right panel: quantification of cell clones; n = 3). <bold>(J)</bold> Representative images of the cell cycle induced by PBS, KN93, MR<sub>52</sub>, or MRK hydrogel per the flow cytometry analyses. <bold>(K)</bold> Quantitative data from <bold>(J)</bold>. Data are presented as the mean ± SEM (n = 4). <bold>(L-M)</bold> Flow cytometry analyses of cell apoptosis induced by PBS, KN93, MR<sub>52</sub>, or MRK hydrogel. Data are presented as the mean ± SEM (n = 3).</p></caption><graphic xlink:href="thnov10p3049g001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p><bold>The MRK hydrogel induces ICD and facilitates intracellular uptake of loaded cargo <italic>in vitro</italic></bold>. <bold>(A, B)</bold> Flow cytometry measurement of ROS induced by PBS, KN93, MR52, or MRK hydrogel. Data are presented as the mean ± SEM (n = 4). <bold>(C)</bold> ATP levels in the B16F10 cells treated with indicated compounds were measured using the multiscan spectrum. Data are presented as mean ± SEM (n = 4). <bold>(D, E)</bold> Flow cytometry analyses of CRT expression on the cell membrane surface. Data are presented as the mean ± SEM (n = 4). <bold>(F)</bold> Representative immunofluorescence staining images of CRT expression (green) on the surface of B16F10 cells after various treatments. Phalloidine-rhodamine (red) indicates the cytoskeleton (scale bar, 20 µm). <bold>(G)</bold> Representative immunofluorescence images of the intake of Cy5 in B16F10 cells treated with MR<sub>52</sub>-Cy5 or free Cy5 at the indicated time points (scale bar, 50 <italic>µ</italic>m). <bold>(H, I)</bold> Flow cytometry analyses of Cy5 uptake in B16F10 cells after MR<sub>52</sub>-Cy5 or free Cy5 treatments at indicated time points. Data are presented as the mean ± SEM (n = 3).</p></caption><graphic xlink:href="thnov10p3049g002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p><bold> Targeting CAMKII to reset TAMs toward antitumor phenotypes. (A, B)</bold> Flow cytometry analyses of the expression of CD206 and CD86 in BMDMs. BMDMs were treated with KN93 (5 <italic>μ</italic>M or 10 <italic>μ</italic>M) for 24 h. Data are presented as the mean ± SEM (n = 3). <bold>(C, D, E, F)</bold> RNA sequencing analyses. BMDMs were cocultured with PBS, KN93 (5 <italic>μ</italic>M), or KN93 (10 <italic>μ</italic>M) for 24 h. RNA was extracted for RNA sequencing, and the sequence data were analyzed. <bold>(C)</bold> A volcano plot showing the up-regulated or insignificantly expressed or down-regulated genes when comparing the KN93 (10 <italic>μ</italic>M)-treated group with the PBS group. <bold>(D)</bold> Heatmaps illustrating the log<sub>2</sub>-fold change of M1- and M2-related gene sets, as indicated. <bold>(E, F)</bold> GO and KEGG enrichment analyses identifying the activation of specific canonical pathways as indicated in BMDMs treated with KN93 (10 <italic>μ</italic>M) or PBS.</p></caption><graphic xlink:href="thnov10p3049g003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p><bold><italic>In vivo</italic> therapeutic effects and immune Activation of the MRK hydrogel. (A)</bold> Photograph of dissected tumor samples in different groups as indicated. <bold>(B)</bold> Tumor growth curves for mice injected intratumorally with PBS, MR<sub>52</sub>, KN93, or MRK hydrogel. Data are presented as the mean ± SEM (n = 7-8).<bold> (C)</bold> Representative bioluminescence images of B16F10 tumors in C57BL/6 mice after various treatments as indicated. <bold>(D)</bold> Quantification of tumor weights in each group. Data are presented as the mean ± SEM (n = 7-8)<bold>. (E)</bold> Flow cytometry gating strategy for the detection ratio of macrophages. <bold>(F-G)</bold> Percentages of the M2/total macrophages <bold>(F)</bold> and M1/M2 ratios <bold>(G)</bold> within the TME of various treatment groups (M1-like TAMs: ZIR<sup>-</sup>CD11b<sup>+</sup>F4/80<sup>+</sup>CD86<sup>+</sup>CD206<sup>-</sup>, M2-like TAMs: ZIR<sup>-</sup>CD11b<sup>+</sup>F4/80<sup>+</sup>CD86<sup>-</sup>CD206<sup>+</sup>). <bold>(H)</bold> Percentages of activated DCs (CD11c<sup>+</sup>CD86<sup>+</sup>) within ILNs. <bold>(I)</bold> Ratios of CD45<sup>+</sup> lymphocytes within the TME in each group. <bold>(J)</bold> Percentages of CD4<sup>+</sup>IFNγ<sup>+</sup> T cells (Th1 cells) within the TME in each group. <bold>(K)</bold> Portions of cytotoxic CD8<sup>+</sup>IFNγ<sup>+</sup> T cells (CTLs) within the TME in each group. Data are presented as the mean ± SEM (n = 8) for (F-K).</p></caption><graphic xlink:href="thnov10p3049g004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p><bold> Combining the MRK hydrogel and the PD-1 antibody exerted synergistic antitumor effects. (A, B)</bold> Detection of PD-L1 expression levels in BMDMs after various treatments, as indicated by flow cytometry. Data are presented as the mean ± SEM (n = 4). <bold>(C)</bold> Schematic illustration of the combination of the MRK hydrogel and PD-1 antibody treatment schedule for subcutaneously implanted B16F10 melanoma model.<bold> (D)</bold> Tumor growth monitored for 12 days in mice after various treatments, as indicated. Data are presented as the mean ± SEM (n = 8). <bold>(E)</bold> The long-term survival in the corresponding treatment groups recorded according to the Kaplan-Meier analysis (n = 8). <bold>(F)</bold> Survival curves for the treated group (receiving three stitches of the MRK hydrogel and four stitches of the PD-1 antibody treatment) and PBS group (n = 9) in the B16F10 melanoma model. <bold>(G)</bold> Survival curves for the treated and controlled mice, as indicated (n = 12) in the B16-luc melanoma model. <bold>(H)</bold> Tumor growth monitored in C57BL/6 mice (n = 9-10) with B16-luc melanoma that were treated with anti-CD8 neutralizing antibody and/or MRK plus anti-PD-1 for 12 days. <bold>(I)</bold> Survival curves for the corresponding treatment groups according to the Kaplan-Meier analysis (n = 9-10).</p></caption><graphic xlink:href="thnov10p3049g005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p><bold> Therapeutic effects of MRK alone and combined with the PD-1 antibody in MAs of the H22 hepatoma model. (A)</bold> Schematic illustration of the MRK hydrogel treatment schedule for the intraperitoneally injected H22-luc hepatoma ascites model. <bold>(B)</bold> Bioluminescence images of H22 hepatoma ascites mice after various treatments, as indicated (n = 7).<bold> (C)</bold> Survival percentages in each group (n = 7).<bold> (D)</bold> Ratios of CD45<sup>+</sup> lymphocytes within ascites in each group. <bold>(E)</bold> Percentages of Th1 cells within ascites in each group. <bold>(F)</bold> Portions of cytotoxic CTLs within ascites in each group. Data are presented as the mean ± SEM (n = 7) for (D-F). <bold>(G)</bold> Schematic illustration of the MRK hydrogel and PD-1 antibody treatment schedule for the H22-luc hepatoma ascites model. <bold>(H)</bold> Survival curves for the treated and controlled mice, as indicated (n = 14).<bold> (I)</bold> Percentages of CR mice in each group (n = 14).</p></caption><graphic xlink:href="thnov10p3049g006"></graphic></fig></floats-group></pmc><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Hubei</li><li>État de New York</li></region><settlement><li>Buffalo (New York)</li><li>Wuhan</li></settlement><orgName><li>Université d'État de New York à Buffalo</li></orgName></list><tree><country name="République populaire de Chine"><region name="Hubei"><name sortKey="Dai, Xiaomeng" sort="Dai, Xiaomeng" uniqKey="Dai X" first="Xiaomeng" last="Dai">Xiaomeng Dai</name></region><name sortKey="Deng, Suke" sort="Deng, Suke" uniqKey="Deng S" first="Suke" last="Deng">Suke Deng</name><name sortKey="Hu, Yan" sort="Hu, Yan" uniqKey="Hu Y" first="Yan" last="Hu">Yan Hu</name><name sortKey="Huang, Jing" sort="Huang, Jing" uniqKey="Huang J" first="Jing" last="Huang">Jing Huang</name><name sortKey="Jin, Honglin" sort="Jin, Honglin" uniqKey="Jin H" first="Honglin" last="Jin">Honglin Jin</name><name sortKey="Li, Yan" sort="Li, Yan" uniqKey="Li Y" first="Yan" last="Li">Yan Li</name><name sortKey="Lu, Lisen" sort="Lu, Lisen" uniqKey="Lu L" first="Lisen" last="Lu">Lisen Lu</name><name sortKey="Meng, Jingshu" sort="Meng, Jingshu" uniqKey="Meng J" first="Jingshu" last="Meng">Jingshu Meng</name><name sortKey="Wan, Chao" sort="Wan, Chao" uniqKey="Wan C" first="Chao" last="Wan">Chao Wan</name><name sortKey="Wu, Gang" sort="Wu, Gang" uniqKey="Wu G" first="Gang" last="Wu">Gang Wu</name><name sortKey="Yang, Kunyu" sort="Yang, Kunyu" uniqKey="Yang K" first="Kunyu" last="Yang">Kunyu Yang</name><name sortKey="Zhang, Lingling" sort="Zhang, Lingling" uniqKey="Zhang L" first="Lingling" last="Zhang">Lingling Zhang</name><name sortKey="Zhang, Zhanjie" sort="Zhang, Zhanjie" uniqKey="Zhang Z" first="Zhanjie" last="Zhang">Zhanjie Zhang</name></country><country name="États-Unis"><region name="État de New York"><name sortKey="Lovell, Jonathan F" sort="Lovell, Jonathan F" uniqKey="Lovell J" first="Jonathan F." last="Lovell">Jonathan F. 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