Chronic Stress Rewires Tumor Immunity Through Intratumor Phages

Chronic stress is associated with poor cancer outcomes, and, while stress can disrupt the gut microbiome, how these stress-induced alterations may influence immune responses in the context of cancer remains incompletely understood. To investigate how chronic stress influences antitumor immunity and potentially reshapes the tumor microenvironment, Bashir and colleagues studied adult mice exposed to chronic unpredictable mild stress over 21 days, comprised of a regimen of two mild stressors a day, including exposure to intervals of food deprivation, white noise, and light during night. By day 7, plasma corticosterone levels were elevated, indicating a physiological response to stress, at which point MC38 colorectal cancer cells or B16F10 melanoma cells were subcutaneously injected. The chronic unpredictable mild stress protocol significantly accelerated tumor growth and impaired germinal center (GC) B-cell responses, consistent with reduced antitumor IgG production. This reduction in GC B-cell responses affected antigen-specific B cells, as mice exposed to chronic stress exhibited significant impairment in response to antigen or to B-cell maturation stimuli. These stress-induced B-cell defects were dependent on the gut microbiome, as broad-spectrum antibiotics abrogated these phenotypes. The gut microbiota of chronically stressed mice were enriched for intratumor levels of the bacterium Enterococcus gallinarum. Mechanistically, chronic stress disrupted intestinal barrier integrity through glucocorticoid receptor signaling in intestinal epithelial cells, enabling translocation of E. gallinarum from the gut into tumors. Tumor-associated E. gallinarum released abundant phage DNA that activated TLR9 signaling and induced glucocorticoid production by cancer-associated fibroblasts (CAF), resulting in increased levels of corticosterone within tumors. Intratumor glucocorticoid signaling directly suppressed GC B-cell fitness, affinity maturation, and antibody responses through the glucocorticoid receptor. Similar findings were observed with phage-containing Klebsiella pneumoniae isolates recovered from human colorectal tumors, and phage enrichment was also detected in published datasets from human brain tumors, suggesting broader relevance across malignancies. Pharmacologic inhibition of intratumor TLR9 or intratumoral elimination of E. gallinarum reduced corticosterone levels, restored GC B-cell responses, and reversed the tumor-promoting effects of chronic stress. These findings reveal a clinically relevant intratumor phage–fibroblast–B cell circuit through which stress suppresses antitumor immunity and identify microbial and immune signaling pathways that may be leveraged to enhance cancer immunotherapy.Bashir H, Sanidad KZ, Ravisankar P, Banks KM, Bose A, Yu S, et al. Chronic stress unleashes an intratumor phage-fibroblast-B cell circuit to promote tumor growth. Cancer Cell 2026;44:1458–76.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.