This study demonstrates that CD4+Tstr cells contribute to the formation of an immunosuppressive microenvironment. Furthermore, the high expression of TNFα by tumor cells in PNI tissues may promote Schwann cell release of CCL4 chemokine, thereby recruiting additional CD4+T cells and exacerbating PNI progression. Consequently, TNFα monoclonal antibodies may enhance the response to PD-1 monoclonal antibody therapy in patients with neuroinvasive colorectal cancer.