[Research progress of Type II immune responses in cancer therapy]

Current cancer immunotherapies primarily focus on eliciting Type I immune responses to combat malignancies, yet their efficacy in solid tumors remains suboptimal. The Type II immune response, predominantly mediated by T helper 2 (Th2) cells, regulates immune reactions to infections, allergies, and tissue repair through cytokine secretion. However, emerging evidence reveals its complex and multifaceted role in the tumor microenvironment (TME), where it can either promote tumor progression by facilitating immune evasion and tumor-associated inflammation or exert anti-tumor effects through distinct immunomodulatory mechanisms. On the one hand, interleukin 4 (IL-4) drives M2 macrophage polarization via signal transducer and activator of transcription 6 (STAT6) signaling, synergizing with the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis to amplify immunosuppression. On the other hand, the Th2-associated factors can reprogram anti-tumor immunity in specific therapeutic context, primarily by activating cytotoxic T lymphocytes (CTLs). Recent studies demonstrate that combined immune checkpoint blockade (ICB) therapy not only enhances CD8⁺ T cell activation and proliferation in tumor-draining lymph nodes by stimulating IL-4 production in follicular helper T (Tfh) cells but also induces IL-5 secretion from CD4⁺ T cells, triggering an IL-33-eosinophil cascade that promotes intratumoral CD8⁺ T cell infiltration and effector function. This "pro-tumor vs. anti-tumor" duality underscores the pivotal yet paradoxical role of Type II immunity in tumor immunoregulation. Here, we systematically review the dual functions of Type II immune responses in tumor immunity and their translational potential for next-generation cancer immunotherapy.