Fig. 3: Regulatory mechanisms of Th cells.

Th cells can be classified according to different secreted factors. Th1 cells mainly secrete IFN-γ, TNF-α, IL-2 and other cytokines, which play a role in inhibiting tumor. In contrast, Th2 cells secrete cytokines such as IL-4, IL-5, and IL-13 that induce T-cell anergic and attenuate T-cell cytotoxicity. LSECs in the liver were able to inhibit IFN-expressing Th1 cells and promote IL-4-expressing Th2 cells. The M1 subtype of TAMs can induce the generation of Th1 cells. In addition, Th2 cells can secrete cytokines such as IL-13 and IL-5 to promote the differentiation of macrophages into M2 type and inhibit the proliferation of CTL. Activated Th cells play a role in killing TCs by supporting the cytotoxic activity of CTLS. Exosomal miR-135a-5p could directly inhibit CD4⁺T-cell activation in a mouse CRC model by activating the LATS2-YAP-MMP7 signaling axis. On the one hand, Th17 cells can secrete a large number of pro-inflammatory factors, keep the liver in a long-term inflammatory state, and further promote tumor progression and metastasis. On the one hand, Th17 cells can affect tumor metastasis by regulating immune cells and cytokines in the microenvironment of liver cancer. Th17 can inhibit IL-2 production, and IL-23 further activates STAT3, RORα, and RORγt in Th17 cells to maintain their long-term inflammatory environment. IL-17 secreted by Th17 cells can stimulate the proliferation of TCs through the IL-6/Stat3 signaling pathway. Th17 cells stimulate angiogenesis by activating ERK and Stat3 pathways and act directly on LSEC to induce tumor angiogenesis, thereby promoting tumor metastasis. Th17 and Th22 can promote tumor angiogenesis by secreting IL-22.