{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:15:22Z","timestamp":1788221722280,"version":"build-2803163510"},"posted":{"date-parts":[[2026,7,1]]},"group-title":"Immunology","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01CA278852"],"award-info":[{"award-number":["R01CA278852"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R43CA287611"],"award-info":[{"award-number":["R43CA287611"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["I01CX001364"],"award-info":[{"award-number":["I01CX001364"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,28]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Approximately 85-90% of colorectal cancers (CRC) are microsatellite stable and resist immune checkpoint inhibitors (ICI). The recent success of intismeran, a lipid nanoparticle (LNP)-delivered mRNA encoding patient-specific tumor antigens, enhances pembrolizumab responses, showing that LNP-delivered nucleic acids can render ICI-resistant tumors responsive by supplying what the tumor microenvironment lacks. Because an IFN-responsive phenotype predicts CRC response to checkpoint blockade and tumor cell PD-L1 represses IFN-I, we asked whether delivering the missing cytokine, rather than antigen, achieves the same conversion. Here we show that PD-1 blockade failed even when initiated before tumor seeding, yet deleting tumor cell PD-L1 abolished colon cancer lung metastasis, implicating a tumor-intrinsic PD-L1 function that antibody blockade does not neutralize. An LNP-encapsulated IFN\u03b12-encoding nanoplasmid (LNP-IFN\u03b12) transfected tumor cells within lung metastases, converting them into a self-sustaining and tumor-restricted IFN\u03b12 source. LNP-IFN\u03b12 suppressed colon cancer lung metastasis in syngeneic and humanized mouse models and sensitized these ICI-resistant tumors to PD-1 blockade. Efficacy improved further with neutralization of co-induced IL6. scRNA-Seq revealed multi-compartment reprogramming: SPP1\n                  <jats:sup>+<\/jats:sup>\n                  macrophages acquired apoptotic signatures as IFN-responsive monocytes replaced them, progenitor-exhausted T cells exited quiescence and expanded, and tumor cells exited a high-cycling state, gained antigen presentation, and shifted away from cuproptosis resistance. The treated microenvironment transcriptionally recapitulated pembrolizumab-responder signatures, positioning LNP-IFN\u03b12 as an off-the-shelf nanomedicine for ICI-resistant CRC.\n                <\/jats:p>","DOI":"10.64898\/2026.06.26.734809","type":"posted-content","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:30:27Z","timestamp":1782937827000},"source":"Crossref","is-referenced-by-count":0,"title":["Multi-compartment immune and tumor cell reprogramming by LNP-IFN\u03b12 overcomes colon cancer immunotherapy resistance"],"prefix":"10.64898","author":[{"given":"Zainab","family":"Tiamiyu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA"},{"name":"VA Augusta Health Care System, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Czabala","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA"},{"name":"VA Augusta Health Care System, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Worthy","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Velasquez","family":"Zarate","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dakota B.","family":"Poschel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA"},{"name":"VA Augusta Health Care System, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendra","family":"Fick","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA"},{"name":"VA Augusta Health Care System, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA"},{"name":"VA Augusta Health Care System, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry R.","family":"Monnig","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richa","family":"Rashmi","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei","family":"Bombin","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla S.","family":"Redd","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA"},{"name":"VA Augusta Health Care System, Augusta, GA"},{"name":"CheMedImmune Inc., Augusta, GA. 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