Although immune checkpoint inhibitors (ICI) have demonstrated clinical activity in multiple tumor types, the majority of patients do not respond to ICI monotherapy. Mounting evidence suggests that ICI-mediated clinical responses rely upon tumor infiltration by T cells that are able to recognize and kill cancer cells. Here, we review therapeutic modalities that have been shown to promote T-cell infiltration into human tumors in studies to date, and discuss emerging data guiding how these modalities can be sequenced in order to optimize T-cell effector function and memory T-cell generation, while minimizing overactivation and potential toxicity.

The lack of preexisting T-cell inflammation in tumors is a major barrier to effective cancer immunity. A deep understanding of the mechanisms that prevent T cells from trafficking into the tumor in a given individual will be critical for tailoring immunotherapy combinations that can overcome resistance to ICI in patients with cancer.