Given the emerging relevance of these targets in human breast cancer, we explored strategies to sustain tumor immunity while mitigating toxicity using these therapeutic modalities.<h4>Methods</h4>Different approaches to combination immunotherapies employing a PI3Kδ inhibitor (PI-3065) with LAG-3 targeting treatments were tested in a mouse model of triple-negative breast cancer to optimize tumor control while limiting irAE.<h4>Results</h4>Systemic targeting of the LAG-3 ligand FGL1 did not provide additional anticancer benefit but markedly worsened irAE. The gene discussed is FGL1; the disease is breast carcinoma.