C57BL/6J mice were challenged with B16F10, followed by treatment with recombinant BAFF (0.5 mg/kg) or vehicle (n = 10 per group) daily beginning on day 7 after tumor implantation. (A) Tumor weights at the time of resection demonstrated significantly decreased tumor weights in the BAFF treatment group. (B) BAFF increases the proportion of B cells and decreases the proportion of CD4+ and CD8+ T cells within the lymph node. (C) BAFF treatment increases central memory cells and decreases naive T cells in the lymph node and TME. (D) BAFF treatment markedly enhances the proportion of CCR6-expressing CD4+ T cells in tumor draining lymph nodes. Expression of CCR6 on CD4+ T cells in lymph nodes parallels an increase in the proportion of Treg, Th1, and Th17 CD4+ T cells within the TME. (E) Treatment of BAFF was associated with the upregulation of IFN-γ+ within a subset of Tregs in the TME, consistent with a “fragile” Treg phenotype. (F) In vivo treatment of B16F10 tumors with recombinant BAFF significantly delays tumor growth. Tumor growth curves for vehicle (blue) and BAFF (red). Mean ± SEM, n = 12 per group. (G) Volcano plot showing significantly upregulated genes in BAFF-treated TIL. n = 3 per group; significance was determined by nSolver’s DE Call function and adjusted using the Benjamini-Yekutieli correction method. Two-tailed unpaired t test were used to compare vehicle and BAFF group weights and cell phenotypes; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.