Chronic Stress Unleashes an Intratumor Phage-Fibroblast-b Cell Circuit to Promote Tumor Growth

Chronic stress disrupts the gut microbiota in patients with cancer; however, how stress-induced microbiota perturbations impact anti-tumor immunity remains unclear. Here, we show that the gut microbiota is required for chronic stress-induced glucocorticoid production, which impairs antigen-specific germinal center B cell responses. In mouse models of colorectal cancer or melanoma, chronic stress promotes translocation of a gut pathobiont, Enterococcus gallinarum (Eg), to tumors. Within tumors, Eg phage DNA induces glucocorticoid production by cancer-associated fibroblasts (CAFs) via TLR9, which suppresses anti-tumor B cell responses through the glucocorticoid receptor. Targeting intratumoral TLR9 or Eg significantly lowers intratumor glucocorticoid levels and reverses the tumor-promoting effects of chronic stress. Extending these findings to human cancer, we identify lytic phages in a Klebsiella pneumoniae isolate from human colorectal tumors that promote tumor growth and detect phage DNA in human brain tumors. Together, our study reveals a chronic stress-induced intratumor phage-CAF-B cell circuit that weakens anti-tumor immunity.