{"title":"Synergistic Antitumor Immunotherapy via Mitochondria Regulation in Macrophages and Tumor Cells by an Iridium Photosensitizer","authors":"Shumeng Li, Hao Yuan, Xiu-Zhi Yang, Xinyu Xu, Wenhao Yu, Yanping Wu, Shankun Yao, Jin Xie, Weijiang He, Zijian Guo* and Yuncong Chen*, ","doi":"10.1021/acscentsci.4c0215610.1021/acscentsci.4c02156","DOIUrl":"https://doi.org/10.1021/acscentsci.4c02156https://doi.org/10.1021/acscentsci.4c02156","url":null,"abstract":"<p >Mitochondrial targeting has emerged as an attractive method for antitumor treatment. However, most of the mitochondria targeted drugs focused on inhibiting tumor cells, while their potential for activation of immune responses in the tumor microenvironment has rarely been described. In this study, we report a photosensitive iridium complex <b>MitoIrL2</b>, which enabled the simultaneous mitochondrial modulation of macrophages and tumor cells to achieve synergistic antitumor immunity. The adjustment of the mitochondrial respiratory chain, HIF-1α, and the NF-κB pathway in macrophages drove the metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis, converting protumor M2 into the antitumor M1 phenotype. Downregulated expression of immunosuppressive checkpoint SIRPα has also been observed on macrophages. Meanwhile, the mitochondrial targeting <b>MitoIrL2</b> enhanced the immunogenic cell death of tumor cells and reversed the immunosuppressive tumor microenvironment, which activated the systemic immune response and established long-term immune memory <i>in vivo</i>. This work illustrates a promising strategy to simultaneously regulate macrophages toward the antitumor phenotype and enhance immunogenic cell death in tumor cells for synergistic antitumor immunotherapy.</p><p >A mitochondrial targeting iridium photosensitizer could achieve direct immune activation of both macrophages and tumor cells, synergistically enhancing antitumor immunity via mitochondrial modulation.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"441–451 441–451"},"PeriodicalIF":12.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c02156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-03-11eCollection Date: 2025-03-26DOI: 10.1021/acscentsci.5c00389
XiaoZhi Lim
{"title":"Researchers Face Challenges Devising a PFAS-Free Future.","authors":"XiaoZhi Lim","doi":"10.1021/acscentsci.5c00389","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00389","url":null,"abstract":"","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"371-375"},"PeriodicalIF":12.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-03-11DOI: 10.1021/acscentsci.5c0038910.1021/acscentsci.5c00389
XiaoZhi Lim,
{"title":"Researchers Face Challenges Devising a PFAS-Free Future","authors":"XiaoZhi Lim, ","doi":"10.1021/acscentsci.5c0038910.1021/acscentsci.5c00389","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00389https://doi.org/10.1021/acscentsci.5c00389","url":null,"abstract":"<p >Academia and industry see mixed results replacing fluorinated chemicals in refrigeration, textiles, and ion-exchange membranes.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"371–375 371–375"},"PeriodicalIF":12.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00389","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Synergistic Antitumor Immunotherapy via Mitochondria Regulation in Macrophages and Tumor Cells by an Iridium Photosensitizer.","authors":"Shumeng Li, Hao Yuan, Xiu-Zhi Yang, Xinyu Xu, Wenhao Yu, Yanping Wu, Shankun Yao, Jin Xie, Weijiang He, Zijian Guo, Yuncong Chen","doi":"10.1021/acscentsci.4c02156","DOIUrl":"10.1021/acscentsci.4c02156","url":null,"abstract":"<p><p>Mitochondrial targeting has emerged as an attractive method for antitumor treatment. However, most of the mitochondria targeted drugs focused on inhibiting tumor cells, while their potential for activation of immune responses in the tumor microenvironment has rarely been described. In this study, we report a photosensitive iridium complex <b>MitoIrL2</b>, which enabled the simultaneous mitochondrial modulation of macrophages and tumor cells to achieve synergistic antitumor immunity. The adjustment of the mitochondrial respiratory chain, HIF-1α, and the NF-κB pathway in macrophages drove the metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis, converting protumor M2 into the antitumor M1 phenotype. Downregulated expression of immunosuppressive checkpoint SIRPα has also been observed on macrophages. Meanwhile, the mitochondrial targeting <b>MitoIrL2</b> enhanced the immunogenic cell death of tumor cells and reversed the immunosuppressive tumor microenvironment, which activated the systemic immune response and established long-term immune memory <i>in vivo</i>. This work illustrates a promising strategy to simultaneously regulate macrophages toward the antitumor phenotype and enhance immunogenic cell death in tumor cells for synergistic antitumor immunotherapy.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"441-451"},"PeriodicalIF":12.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-03-10eCollection Date: 2025-03-26DOI: 10.1021/acscentsci.5c00387
April L Lukowski
{"title":"Promiscuity in Nature Extends to Central Protein Biosynthetic Machinery.","authors":"April L Lukowski","doi":"10.1021/acscentsci.5c00387","DOIUrl":"10.1021/acscentsci.5c00387","url":null,"abstract":"","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"379-381"},"PeriodicalIF":12.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-03-10DOI: 10.1021/acscentsci.5c0038710.1021/acscentsci.5c00387
April L. Lukowski,
{"title":"Promiscuity in Nature Extends to Central Protein Biosynthetic Machinery","authors":"April L. Lukowski, ","doi":"10.1021/acscentsci.5c0038710.1021/acscentsci.5c00387","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00387https://doi.org/10.1021/acscentsci.5c00387","url":null,"abstract":"<p >Thioesters, rather than oxo-esters, can be tolerated and processed during translation to incorporate unnatural monomers.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"379–381 379–381"},"PeriodicalIF":12.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00387","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-03-10eCollection Date: 2025-03-26DOI: 10.1021/acscentsci.4c01021
Jinxuan Zhao, Yi Li, Naohiro Terasaka, Haruo Aikawa, Hiroaki Suga
{"title":"Diversity Scale of Library Matters: Impact of mRNA Library Diversity Scales on the Discovery of Macrocyclic Peptides Targeting a Protein by the RaPID System.","authors":"Jinxuan Zhao, Yi Li, Naohiro Terasaka, Haruo Aikawa, Hiroaki Suga","doi":"10.1021/acscentsci.4c01021","DOIUrl":"10.1021/acscentsci.4c01021","url":null,"abstract":"<p><p>Macrocyclic peptides make up a unique class of modalities known for their high affinity, specificity, and ability to modulate protein-protein interactions, including receptor activation. Messenger RNA display, including the Random Nonstandard Peptides Integrated Discovery (RaPID) system, stands out in identifying target-specific macrocyclic peptides, producing potent binders with low to subnanomolar dissociation constants against diverse targets. It has often been discussed that this success is partly attributed to the vast library of over a trillion different peptide sequences expressed from the corresponding mRNA sequences. However, the impact of library scales on the identification of various binders has not been experimentally validated. Here, we report the RaPID selections against an ectodomain of a receptor tyrosine kinase MET using peptide libraries ranging from 10<sup>6</sup> to 10<sup>14</sup> unique members of mRNAs. We thoroughly analyzed the outcomes, including the binding kinetic properties, of the enriched peptide families. This study provides valuable guidelines for designing libraries with various numbers of sequences and selection conditions to enrich macrocyclic peptides with the desired characteristics.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"431-440"},"PeriodicalIF":12.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-03-09DOI: 10.1021/acscentsci.4c0102110.1021/acscentsci.4c01021
Jinxuan Zhao, Yi Li, Naohiro Terasaka, Haruo Aikawa and Hiroaki Suga*,
{"title":"Diversity Scale of Library Matters: Impact of mRNA Library Diversity Scales on the Discovery of Macrocyclic Peptides Targeting a Protein by the RaPID System","authors":"Jinxuan Zhao, Yi Li, Naohiro Terasaka, Haruo Aikawa and Hiroaki Suga*, ","doi":"10.1021/acscentsci.4c0102110.1021/acscentsci.4c01021","DOIUrl":"https://doi.org/10.1021/acscentsci.4c01021https://doi.org/10.1021/acscentsci.4c01021","url":null,"abstract":"<p >Macrocyclic peptides make up a unique class of modalities known for their high affinity, specificity, and ability to modulate protein–protein interactions, including receptor activation. Messenger RNA display, including the Random Nonstandard Peptides Integrated Discovery (RaPID) system, stands out in identifying target-specific macrocyclic peptides, producing potent binders with low to subnanomolar dissociation constants against diverse targets. It has often been discussed that this success is partly attributed to the vast library of over a trillion different peptide sequences expressed from the corresponding mRNA sequences. However, the impact of library scales on the identification of various binders has not been experimentally validated. Here, we report the RaPID selections against an ectodomain of a receptor tyrosine kinase MET using peptide libraries ranging from 10<sup>6</sup> to 10<sup>14</sup> unique members of mRNAs. We thoroughly analyzed the outcomes, including the binding kinetic properties, of the enriched peptide families. This study provides valuable guidelines for designing libraries with various numbers of sequences and selection conditions to enrich macrocyclic peptides with the desired characteristics.</p><p >The initial sampling of the sequence space determines the evolution of the families by the RaPID selection pressure for slow dissociation rates.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 3","pages":"431–440 431–440"},"PeriodicalIF":12.7,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c01021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-03-07DOI: 10.1021/acscentsci.5c0035710.1021/acscentsci.5c00357
Grace C. Thaggard, and , Natalia B. Shustova,
{"title":"COFs in the Game: Harvest Water to Sustain","authors":"Grace C. Thaggard, and , Natalia B. Shustova, ","doi":"10.1021/acscentsci.5c0035710.1021/acscentsci.5c00357","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00357https://doi.org/10.1021/acscentsci.5c00357","url":null,"abstract":"<p >Breakthrough covalent-organic frameworks can harvest water directly from air at record-low humidity, paving the way for clean drinking water in arid regions.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"653–655 653–655"},"PeriodicalIF":12.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-03-07eCollection Date: 2025-05-28DOI: 10.1021/acscentsci.5c00357
Grace C Thaggard, Natalia B Shustova
{"title":"COFs in the Game: Harvest Water to Sustain.","authors":"Grace C Thaggard, Natalia B Shustova","doi":"10.1021/acscentsci.5c00357","DOIUrl":"10.1021/acscentsci.5c00357","url":null,"abstract":"<p><p>Breakthrough covalent-organic frameworks can harvest water directly from air at record-low humidity, paving the way for clean drinking water in arid regions.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"653-655"},"PeriodicalIF":12.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}