Defining the Stress–Gut Microbiome Interplay in Anti-Tumor B Cell Response

Introduction/Rationale: Chronic psychological stress is a major driver of cancer progression, yet its effects on anti-tumor B cell immunity remain unclear. Activation of the hypothalamic–pituitary–adrenal axis elevates glucocorticoids that broadly suppress immune responses. Given that the gut microbiota supports germinal center (GC) B cell differentiation, stress-induced dysbiosis may impair B cell–mediated tumor immunity.

Methods: Mice were subjected to a 21-day chronic unpredictable mild stress (CUMS) regimen. MC38 or B16F10 tumor cells were implanted on day 7, and tumor growth was monitored. Microbiota dependence was tested using broad-spectrum antibiotics, germ-free housing, and monocolonization. Tumor-associated bacteria were isolated and identified by culturomics, 16S rRNA sequencing, and whole-genome analysis to detect prophage activation. CAFs were stimulated with bacterial DNA ± TLR9 antagonist. Interventions included intratumoral TLR9 blockade and localized antibiotic treatment. Human colorectal tumors were analyzed for intratumor corticosterone and GC B cell abundance.

Results: Chronic stress significantly accelerated tumor growth and suppressed GC B cell responses. These effects were abrogated under antibiotic or germ-free conditions, indicating microbiota dependence. Stress enabled translocation of a gut pathobiont into tumors, where its phage-derived DNA activated TLR9 in cancer-associated fibroblasts, inducing local corticosterone synthesis. This intratumor glucocorticoid suppressed GC B cells and antibody responses. Blockade of the phage–TLR9 pathway restored B cell activity and prevented stress-induced tumor progression. Human colorectal tumors exhibited elevated corticosterone and reduced GC B cells, supporting clinical relevance.

Conclusion: Chronic stress triggers a microbiota-dependent phage–TLR9–glucocorticoid circuit that suppresses B cell immunity and accelerates tumor growth. Targeting this axis restores anti-tumor B cell function and mitigates stress-driven cancer progression.