A novel microprotein HDSP encoded by HOXA10-HOXA9 triggers progression of gastric cancer through maintaining the stability of MECOM and activating MECOM /SPINK1-/EGFR signaling

The presence of noncanonical open reading frames within lncRNAs suggests their potential for translation, yielding various functional peptides or proteins. However, the existence and specific roles of these products in gastric cancer remain largely unexplored. Here we identify the HOXA10-HOXA9-derived small protein (HDSP) in gastric cancer through comprehensive analysis and experimental validation, including mass spectrometry and western blotting. HDSP exhibits high expression and oncogenic roles in gastric cancer. Mechanistically, HDSP blocks TRIM25-mediated ubiquitination and degradation by interacting with MECOM, leading to MECOM accumulation and enhanced SPINK1 transcription-a gene promoting cancer via the EGFR signaling pathway. Furthermore, MECOM fosters HOXA10-HOXA9 transcription, establishing a feedback loop activating SPINK1-EGFR signaling. HDSP knockdown inhibits tumor growth in a PDX model, and infusion of an artificially synthesized HDSP peptide as a neoantigen enhances immune cell-mediated anti-tumor efficacy against gastric cancer in vitro and in vivo. These findings propose HDSP as a potential therapeutic target or neoantigen candidate for gastric cancer treatment.