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Clinically,\n                    <jats:italic>CALR<\/jats:italic>\n                    -mutated MPNs affect younger patients, exhibit thrombocytosis and progressive anemia, and, in MF patients, are associated with a superior survival compared with\n                    <jats:italic>JAK2<\/jats:italic>\n                    - or\n                    <jats:italic>MPL<\/jats:italic>\n                    -mutated disease, yet responses to hydroxyurea and ruxolitinib remain inferior. The C-terminal motif shared between CALR mutations is presented extracellularly on major histocompatibility complex (MHC) Class I molecules and in complex with the thrombopoietin receptor enabling targeting with vaccination and antibody based therapeutic platforms, respectively. Mutant CALR peptide vaccines induce T cell responses but have failed to result in hematologic or molecular responses. Mutant CALR-specific monoclonal antibodies, such as Fc-silent antagonists, can block mutant-CALR\u2013MPL signaling, suppress hematopoietic stem and progenitor cells (HSPC) proliferation and megakaryopoiesis, and achieve rapid, durable hematologic remissions with minimal toxicity in early-phase trials. Preclinical antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell (CAR-T) cells also show potent, selective mutant-cell killing. Here we review the basis and ongoing translational and clinical efforts in the development of CALR-targeted immunotherapies that offer a potential shift from symptom management to disease-modifying treatment in this molecularly defined MPN subset.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-03115-w","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T11:47:38Z","timestamp":1787053658000},"page":"2107-2117","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Immunotherapeutic targeting of calreticulin mutant myeloproliferative neoplasms"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7525-3387","authenticated-orcid":false,"given":"Charles","family":"Hertz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Spyrou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6564-6732","authenticated-orcid":false,"given":"Ronald","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cansu","family":"Cimen Bozkus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Bhardwaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4719-7192","authenticated-orcid":false,"given":"Douglas","family":"Tremblay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Kremyanskaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8400-0483","authenticated-orcid":false,"given":"John","family":"Mascarenhas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"3115_CR1","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1182\/blood-2016-10-695957","volume":"129","author":"E Rumi","year":"2017","unstructured":"Rumi E, Cazzola M. 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