The complex role of calreticulin and its fragments in cancer biology

Abstract Calreticulin (CRT) is a highly conserved Ca 2 + binding chaperone that regulates calcium homeostasis, protein folding, and immune regulation, among numerous functions. In cancer, CRT has emerged as a context-dependent regulator with tumor-promoting and antitumor activities. Intracellular CRT is frequently overexpressed in several malignancies and is often associated with tumor progression, whereas surface-exposed CRT acts as a damage-associated molecular pattern (DAMP) that promotes immunogenic cell death and enhances antitumor immune responses. In contrast, soluble and mutant forms of CRT can contribute to immune evasion and tumor progression. Analyses of transcriptomic and proteomic cancer databases support the context-dependent role of CRT, showing tumor-specific differences in its expression and prognostic associations. Parasite-derived CRT homologs, particularly from Trypanosoma cruzi and Taenia solium , exhibit potent antitumor effects in experimental models, in some cases exceeding those of human CRT, highlighting structural and functional divergence across species. Additionally, CRT-derived fragments, such as vasostatin, exhibit strong antiangiogenic and antitumoral properties, whereas other fragments may induce immunosuppressive signaling pathways that promote tumor growth. This review summarizes evidence on the contrasting roles of mammalian and parasitic full-length CRT and their derived fragments in tumor biology, emphasizing molecular mechanisms, clinical and database evidence, and emerging therapeutic approaches targeting CRT. The potential advantages of parasite-derived CRT and its fragments are considered alongside limitations related to immunogenicity, structural differences, production, and safety. Understanding the mechanisms underlying these context-dependent effects may facilitate the development of CRT-directed therapeutic strategies, including the use of its fragments and their combination with existing anticancer therapies.