Oncolytic Probiotics with Molecular Pili for Solid Tumor Therapy.

Cell therapy and oncolytic viruses have emerged as promising cancer treatments but face significant challenges in solid tumors due to immune suppression and gene-related toxicities. Here, we selected a probiotic Lactobacillus rhamnosus (LR) that appears to exert oncolytic activity by inducing massive calcium influx, which subsequently triggers a lethal ROS burst in tumor cells. To reduce systemic toxicity and enhance oncolytic efficacy at the tumor site, we designed molecular pili (MP) targeting collagen-rich solid tumors and modified them into LRs via chemical coupling (LR@MP). In mouse models of colorectal cancer and melanoma, LR@MP increased intratumoral accumulation by two times and enhanced bacterial clearance from peripheral tissues. At a safe dose of 4 × 10 CFU, LR@MP inhibited 60%-80% of tumor growth. This dual-optimization strategy provides a new approach for next-generation in vivo therapies and warrants further preclinical evaluation.