Challenges in the Evolving Role of Calreticulin as a Promising Target for Precision Medicine in Myeloproliferative Neoplasms

More than a decade after its discovery, advances have been made in understanding the oncogenic role of mutant <i>CALR</i> in <i>BCR::ABL1</i>-negative myeloproliferative neoplasms (MPNs). Disease biology has proven to be distinct from other MPN subtypes, with meaningful differences that have created opportunities for therapeutic targeting of <i>CALR</i>-mutant clones. Among the approaches under investigation, immunotherapy has advanced furthest into clinical development and holds promise. Several strategies are now being explored, including monoclonal antibodies directed against the CALR neoepitope, T-cell-redirecting bispecific antibodies, precision antibody-drug conjugates, vaccination approaches, and CAR T-cell therapies. Early-phase clinical trials with fully human anti-CALR monoclonal antibodies (e.g., INCA033989) have shown very promising hematologic and molecular responses with manageable toxicity. In preclinical models, bispecific antibodies and CAR T-cell therapy offer additional avenues to exploit the selective cell-surface localization of mutant CALR. By contrast, vaccination strategies have so far demonstrated limited clinical efficacy, and their potential in clinical practice remains challenging. At the same time, the complexity of <i>CALR</i>-driven disease raises key questions, including whether anti-CALR therapies can shift treatment goals beyond thrombotic risk reduction, how best to monitor clonal burden, and how to address immune escape. In this review, we highlight the latest therapeutic advances in <i>CALR</i>-mutated MPNs while outlining the critical unmet needs that will shape the future of care for these patients.