EV-Associated HOTAIR in Cancer Cell Communication: A Distance-Aware Review of Functional Transfer Claims

Abstract

HOTAIR is classically defined as an intracellular long non-coding RNA that scaffolds PRC2/LSD1 to remodel chromatin and functions as a competing endogenous RNA. Its detection in extracellular vesicles (EVs) and circulating biofluids has extended this view towards intercellular and potentially systemic roles in cancer. However, EV-associated RNA claims often combine evidence obtained at different biological scales, making it difficult to distinguish functional cell-to-cell transfer from circulating detection. Here, we read the HOTAIR literature through a distance-aware reading lens, a descriptive interpretive aid rather than an established evidence taxonomy, that separates intracellular activity (D0), paracrine or microenvironmental transfer (D1), and systemic circulation (D2). At each scale, we ask whether the receiving cell or tissue has been functionally validated. Within selected D0-D1 contexts, EV-associated HOTAIR has been implicated in local recipient-cell reprogramming, including effects on B cells, macrophages, endothelial cells and stromal or tumour cells through metabolic, transcriptional and signalling routes. Several mechanistically distinct pathways recur on checkpoint-associated and immunosuppressive endpoints, particularly PD-L1-linked phenotypes; we describe this as a recurrent checkpoint-associated convergence pattern rather than as a new biological paradigm. Circulating HOTAIR remains a valuable discovery and monitoring signal; however, claims that it functions as a distal messenger should be qualified unless downstream recipient-cell function, cytosolic delivery and causal continuity are demonstrated. Circulation-scale studies can motivate productive paracrine-and intracellular-scale follow-ups even when distal function is not established. We describe the mismatch between abundant detection and insufficient demonstrated functional continuity as an evidential trough. This review therefore positions EV-associated HOTAIR as a useful case for matching cancer cell communication claims to the scale and quality of evidence that supports them while preserving the biomarker value of circulating RNA studies.