J. Clin. Invest. 130, 2570–2586 (2020)

Adaptive resistance of tumors is a major impediment to the efficacy of checkpoint inhibition therapies such as anti-PD-1. In The Journal of Clinical Investigation, Hanks and colleagues use several murine cancer models of anti-PD-1 treatment to decipher a new pathway of adaptive resistance. Anti-PD-1 treatment results in activation of CD8+ T cells in the tumor microenviroment; however, this response is transient and the tumors ultimately evade control. T cell activation instead triggers a PD-L1- and interferon-γ-dependent pathway in the tumor cells. This results in tumor-intrinsic activation of the NLRP3 inflammasome that ultimately leads to the production of chemokines responsible for the recruitment of immunosuppressive granulocytic myeloid-derived suppressor cells (PMN-MDSCs) that blunt the anti-tumor CD8+ T cell response. Inhibition of NLRP3 activity increases the efficacy of anti-PD-1 treatment in these murine models. These findings identify several potentially druggable targets that could be investigated to complement anti-PD-1-based immunotherapies.