ESOHISTO proposes a radically new scientific concept to revolutionize disease research, diagnosis and treatment by real-time imaging of 3D organization of diseased cells, cell-cell and cell-matrix interactions, and their biochemical events in large living human tissue/organs. This transformative vision of 'in vivo histology and histochemistry' is not yet feasible for most human organs. However, GI mucosa, the shallow lining of GI tract where many GI cancer originates, is a unique tissue to implement the ambitious vision of ESOHISTO by developing disruptive endosocpic technologies to provide a long-awaited solution to the insufficient diagnosis and early detection of GI cancers. The landscape changing ability of ESOHISTO is attributed to its key invention of a volumetric-projection confocal laser endomicroscopy (VP-CLE) and a multimodal approach to complement VP-CLE with advanced imaging methods including optical coherence tomography (OCT) and optoacoustic mesoscopy (OPAM). The novel volumetric projection method allows VP-CLE to provide 3D cellular features and molecular profiles at high speed and without any mechanic parts in the distal endoscope. OCT and OPAM delivers 3D morphology and pathophysiology of GI mucosa with an imaging depth far exceeding microscopy. The combination of VP-CLE, OCT and OPAM in a miniaturized endoscope heralds a paradigm-shifting GI cancer diagnosis scheme by replacing insensitive white light endoscopy and biopsy with comprehensive 3D OCT/OPAM inspection to identify subtle lesions and following 'zoom-in' cellular/molecular vision through VP-CLE to complete in vivo diagnosis. With its prospect of unprecedented 'in vivo histology and histochemistry' for GI cancer diagnosis and early detection, ESOHISTO is able to leverage European investment and know-how and strengthen EU citizens' well-being and economic growth by leading the market position in future GI endoscopic imaging.