Linking sORFs and microproteins in hematological malignancies: current update on origin, function and clinical implications

Advances in integrated translatomics and proteomics techniques have successfully identified the hidden layer of the microproteome that has historically been regarded as non-coding. Investigations into the involvement of microproteins in hematological malignancies may help address the key gaps that persist despite extensive genomic and transcriptomic profiling. Many blood cancers display extensive clonal heterogeneity, dynamic evolution, and limited actionable mutations. Consequently, mutation-centric approaches are insufficient to fully elucidate disease behavior and identify novel treatment methods. Understanding the role of microproteins may help clarify the relationship between aberrant non-coding RNA expression and observed phenotypes in malignant cells, by finding the direct key contributors to signaling, metabolic rewiring, and epigenetic regulation. These tiny molecules may uncover an unexplored reservoir of disease regulators and potential antigenic targets for immunotherapy. Antigenic microproteins, arising from unconventional coding regions such as ncRNA transcripts, may elicit T-cell responses and represent a previously unrecognized class of immunogenic molecules with therapeutic relevance. This review highlights the need for exploration of the role of microproteins in pathobiology of hematological malignancies and provides a framework to support future studies evaluating the immunogenic potential of microproteins as antigenic targets.