Our study provides unprecedented insights into the remodelling of the TME of human tumours exposed to PI3K/mTORi and/or PD‐1 blockade within the context of a multilineage human immune system, and a rationale for combining PI3K/mTOR inhibitors and PD‐1 blockade as a promising therapy for treating of pS6high uLMS. The gene discussed is PIK3CA; the disease is neoplasm.