UC San Diego

Colorectal cancer is characterized by a fibrotic phenotype that makes solid tumors hard to treat. The overexpressed and dysregualted extracellular matrix limits the delivery of therapeutics and the infiltration of immune cells, presenting a physical barrier that inhibit or dampen therapeutic effects and full tumor perfusion. Here we show that introducing quorum-regulated collagenase expression into attenuated Salmonella typhimurium enables bacteria to remodel this barrier from within the tumor and improve its own colonization efficiency. We demonstrate that collagenase expression under LuxI/LuxR quorum-sensing control produces density-dependent ECM disruption in CRC spheroids and significantly enhances intratumoral bacterial penetration at physiologically relevant seeding densities. We establish a patient-derived organoid co-culture platform using matched tumor and normal colon tissue from microsatellite-stable and microsatellite-instable CRC patients, and show that Salmonella achieves tumor-selective colonization that is coupled to quantifiable morphological and transcriptional responses. When the collagenase strain is co-administered in consortia (i.e. with a therapeutic proxy strain), it significantly enhances partner colonization in patient-derived CRC organoids from both molecular subtypes. A pilot in vivo study in the MC38 syngeneic model shows directional trends toward reduced intratumoral collagen and improved immune cell penetration depth. These findings support a therapy primer strategy in which an ECM-remodeling bacterial strain sensitizes the tumor microenvironment to amplify the efficacy of existing therapeutic modalities without requiring new agents.