To better harness the beneficial functions of CD4+ T cells while mitigating their suppressive effects in cancer immunotherapy, a multifaceted approach is required. One strategy is to selectively target and expand tumor-specific effector CD4+ T cells that promote antitumor immunity while minimizing the activation of regulatory CD4+ T cell subsets like Tr1 cells. This can be achieved through personalized vaccine strategies that focus on inducing and amplifying effector CD4+ T cell responses against tumor-specific antigens. Additionally, combination therapies that target multiple checkpoints, such as PD-1 and LILRB4, can help overcome the inhibitory signals mediated by suppressive CD4+ T cell subsets. Furthermore, modulating the tumor microenvironment to favor the recruitment and activation of effector CD4+ T cells, while inhibiting the suppressive mechanisms of regulatory CD4+ T cells, can enhance the overall antitumor immune response. By carefully balancing the activation and regulation of CD4+ T cell subsets, we can optimize cancer immunotherapy outcomes and improve patient responses.