With the emergence and success of checkpoint blockade immunotherapy, immuno-oncology has primarily focused on CD8 T cells, whose cytotoxic programs directly target tumor cells. However, the limited response rate of current immunotherapy regimens has prompted investigation into other types of tumor-infiltrating immune cells, such as CD4 T cells and B cells, and how they interact with CD8 T cells in a coordinated network. Recent studies have demonstrated the potential therapeutic benefits of CD4 T follicular helper (TFH) cells and B cells in cancer, highlighting the important role of their crosstalk and interactions with other immune cell components in the tumor microenvironment. These interactions also occur in tumor-associated tertiary lymphoid structures (TLS), which resemble secondary lymphoid organs (SLOs) with orchestrated vascular, chemokine, and cellular infrastructures that support the developmental pathways of functional immune cells. In this review, we discuss recent breakthroughs on TFH biology and T cell-B cell interactions in tumor immunology, and their potential as novel therapeutic targets to advance cancer treatment.