A study published in Nature (DOI: 10.1038/s41586-024-07752-y) reveals that CD4+ T cells, specifically type 1 regulatory T (Tr1) cells, can suppress cancer immunotherapy. These Tr1 cells, which express IL-10, granzyme B, perforin, CCL5, and LILRB4, are induced by high-dose MHC-II neoantigen (neoAg) vaccines (HDVax) and inhibit tumor rejection. In contrast, low-dose MHC-II neoAg vaccines (LDVax) promote tumor rejection. The study shows that HDVax-induced Tr1 cells selectively kill MHC-II-expressing antigen-presenting cells, such as conventional dendritic cells (cDC1s), reducing their numbers in tumors and impairing antitumor immune responses. Strategies to overcome this inhibition include anti-LILRB4 blockade, CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. The findings demonstrate that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumor responses, thereby impeding immune control of cancer. The study highlights the importance of MHC-II neoAg dosing in vaccine efficacy and provides strategies to circumvent the inhibitory effects of high-dose MHC-II neoAg on antitumor responses. The results suggest that Tr1 cells, which become detectable in progressively growing tumors resistant to anti-PD1 therapy, are physiologically relevant participants in cancer-related immunosuppression. The study also identifies LILRB4 as a marker of inhibitory CD4+ T cells and shows that anti-LILRB4 treatment can reverse suppression by Tr1-like cells. The findings have implications for improving the effectiveness of cancer immunotherapies by targeting Tr1 cells and their inhibitory mechanisms.A study published in Nature (DOI: 10.1038/s41586-024-07752-y) reveals that CD4+ T cells, specifically type 1 regulatory T (Tr1) cells, can suppress cancer immunotherapy. These Tr1 cells, which express IL-10, granzyme B, perforin, CCL5, and LILRB4, are induced by high-dose MHC-II neoantigen (neoAg) vaccines (HDVax) and inhibit tumor rejection. In contrast, low-dose MHC-II neoAg vaccines (LDVax) promote tumor rejection. The study shows that HDVax-induced Tr1 cells selectively kill MHC-II-expressing antigen-presenting cells, such as conventional dendritic cells (cDC1s), reducing their numbers in tumors and impairing antitumor immune responses. Strategies to overcome this inhibition include anti-LILRB4 blockade, CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. The findings demonstrate that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumor responses, thereby impeding immune control of cancer. The study highlights the importance of MHC-II neoAg dosing in vaccine efficacy and provides strategies to circumvent the inhibitory effects of high-dose MHC-II neoAg on antitumor responses. The results suggest that Tr1 cells, which become detectable in progressively growing tumors resistant to anti-PD1 therapy, are physiologically relevant participants in cancer-related immunosuppression. The study also identifies LILRB4 as a marker of inhibitory CD4+ T cells and shows that anti-LILRB4 treatment can reverse suppression by Tr1-like cells. The findings have implications for improving the effectiveness of cancer immunotherapies by targeting Tr1 cells and their inhibitory mechanisms.