Abstract CD4+ TFH cells provide help to B cells, which is critical for germinal center (GC) formation. Although the presence of these cells is correlated with favorable clinical outcomes in various cancer types, little is known about how TFH and B cells function in anti-tumor immunity. Through the analyses of survival and bulk expression data in The Cancer Genome Atlas (TCGA) and single cell RNA sequencing data, we found that TFH cells correlated with GC B cells and with prolonged survival of lung adenocarcinoma (LUAD) patients. To further investigate if and how TFH-B cell interactions evoke protective anti-tumor responses, we developed the KP-HELLO murine lung adenocarcinoma model, in which tumor cells expressed B-cell- and T-cell-recognized neoantigens (HEL, LCMV GP33–43/FLAG/GP61–80, and codon-Optimized mScarlet). KP-HELLO tumors triggered tumor-specific TFH and GC B cell responses, which were necessary for tumor control, as were effector CD8+ T cell responses. The latter were reduced in the absence of T cell-B cell interactions or the IL-21 receptor. IL-21 was produced primarily by TFH cells, development of which required B cells. Moreover, development of tumor-specific TFH cell-responses was also reliant upon tumors that expressed B-cell-recognized neoantigens, which suggested that tumor-neoantigens themselves can control the fate decisions of tumor-specific CD4+ T cells by facilitating interactions with tumor-specific B cells. Our data highlight the importance of B cell-TFH cell collaborations in driving anti-tumor CD8+ T cell responses via IL-21 and indicated that therapeutics targeting B cell-TFH cell-IL-21 axis may be beneficial in patients with lung and other cancers.