Lastly, we show that chemotherapeutic and ICB resistance of neoplasms dominated by PD-1hiTim-3+TOX+TCF-1−CD8+ Tex-term and PD-L1+ tCSC presence in the TME are effectively overcome by strategized combination with NeoAg vaccination, provided the newly recruited effector tumor-specific CD8+ T cells are helped by CD4+ T cells. Here, CD4 is linked to neoplasm.