Context-dependent anti-tumor functions of CD4 ⁺ T cells. (A) Within lymphoid tissues, CD4⁺ T cells are critical for licensing cross-presenting DCs, which is via CD40L in tumor-draining lymph nodes. CD4⁺ T cells can also directly activate memory CD8⁺ T cells via CD40 and IL2/IL21. Tfh CD4⁺ T cells activate anti-tumor B cells in draining lymph nodes and in the spleen. (B) Within tumors, CD4⁺ T cells in tumors enhance tumoricidal functions of various innate and adaptive immune effectors. These include macrophages, eosinophils, NK cells, and CD8⁺ T cells. CD4⁺ T cells can also directly kill tumor cells. CD4⁺ T cells are also known to activate B cells in tumors, which have been correlated with favorable responses after checkpoint blockade immunotherapy. Created in BioRender. https://BioRender.com/p44y970. NK, natural killer; PFN, perforin; Gzm; granzyme; p-MHC, peptide-MHC.