J. Clin. Invest. https://doi.org/10.1172/JCI120888 (2018)

Myeloid-derived suppressor cells (MDSCs) within tumors block the anti-tumor action of immune effector cells. In The Journal of Clinical Investigation, Alissafi et al. show that MDSCs rely on autophagy–lysosomal pathways to promote immunosuppression. Tumor growth is diminished in mice with myeloid cell–specific deletion of Atg5, which encodes a key component of autophagy. ATG5-deficient myeloid cells still accumulate in tumors but promote anti-tumor responses by their increased expression of major histocompatibility complex class II and co-stimulatory molecules and decreased suppressor activity. Interfering with the fusion of autophagosomes with lysosomes or lysosomal function also impairs the suppressor activity of MDSCs. Thus, interfering with the autophagy program represents an ‘Achilles’ heel’ through which to target MDSCs to enhance anti-tumor immune responses.