The arch-nemesis to cancer immunotherapies (checkpoint, cytokine, genetic/epigenetic, cellular) is not the cancer, but one of the immune system's own: the regulatory T-cells (Tregs).
They are the counterbalance to the powerful and destructive helper and cytotoxic T-cells: the Yin to the Yang, the Dark side to the Light. Good for tolerising autoimmunity and transplant, bad for eradicating cancer and infection.
It is not easy to target and isolate them. They share the same che...ckpoints (CTLA4, PD-1), are stimulated by the same cytokines (IL2), and they can powerfully neutralise even powerfully activated helper/cytotoxic/NK T-cells.
Not easy, but not impossible. The TIGIT checkpoint can be targeted. So can FOXP3. But overdo it, and autoimmunity can kill too.