Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing
long-term, durable responses for a subset of patients with advanced cancers. Increasingly, research
has identified links between the immune system and critical oncogenic growth factor pathways.
The phosphoinositide 3-kinase (PI3K)-AKT-mTOR cascade is frequently hyperactivated in
cancer, and plays an integral role in many cellular processes including tumour growth and survival
and can underlie resistance to therapies.
In this review, we first summarize two key learnings from the initial studies of inhibitors of this
pathway, including the profile of immune-related adverse events such as colitis, transaminitis and
pneumonitis and the increased incidence of infections with the majority of agents that target the
PI3K-AKT-mTOR pathway. We then discuss recent advances in our understanding of the role of
this pathway in the tumour micro-environment, and in the regulation of innate and adaptive immune
responses, and propose synergistic combination strategies with PI3K-network inhibitors and cancer