Unlocking the Potential of Trichoderma reesei as a Super‐Host for Heterologous Protein Production: Challenges, Advances, and Perspectives

ABSTRACT Trichoderma reesei , a filamentous fungus renowned for its exceptional secretion of cellulase. Its robust secretory capacity has sparked interest in its use as a host for producing heterologous proteins. However, yields of heterologous proteins remain critically low, presumably attributed to proteolytic degradation and the incompatibility of their robust transcription and secretory machinery, highly optimized for native cellulases with non‐native proteins. Strategies to enhance production are analyzed by reviewing nearly all the efforts, including promoter engineering to balance transcriptional strength with secretory capacity, signal peptide screening to modulate ER translocation efficiency, and fusing carrier proteins to bypass secretion bottlenecks. Proteolytic degradation as a major barrier has been mitigated through multi‐protease gene deletions, synergized with process optimization approaches like culture pH optimization and protease inhibitors. Additionally, the drawbacks of key strategies are critically analyzed, emphasizing the need for empirical validation of improvements and limitations for some strategies—or risk exclusion—before implementing specific approaches. Future research should focus on persistently developing genetically optimized strains with minimized protease activity, streamlined secretion pathways, and enhanced genetic manipulability. By systematically addressing these challenges, T. reesei could be engineered into a highly efficient host for the production of valuable proteins—from biofuels to therapeutics, advancing sustainable biomanufacturing.