Obstacles for T-lymphocytes in the tumour microenvironment: therapeutic challenges, advances and opportunities beyond immune checkpoint

The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours. However, metabolic constraints and soluble factors that exist within the TME exacerbate the functional exhaustion of tumour-infiltrating T-cells. Here we review these multifactorial constraints and mechanisms - elevated immunosuppressive metabolites and enzymes, nutrient insufficiency, hypoxia, increased acidity, immense amounts of extracellular ATP and adenosine, dysregulated bioenergetic and purinergic signalling, and ionic imbalance - that operate in the TME and collectively suppress T-cell function. We discuss how scientific advances could help overcome the complex TME obstacles for tumour-infiltrating T-lymphocytes, aiming to stimulate further research for developing new therapeutic strategies by harnessing the full potential of the immune system in combating cancer.Ministry of Education (MOE)Ministry of Health (MOH)Nanyang Technological UniversityNational Medical Research Council (NMRC)National Research Foundation (NRF)Published versionThis research was supported, in part, by the Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 2 (MOE2017-T2-2-004) and Tier 1 (2020-T1-001-062) grants, and the National Research Foundation Singapore under its Open Fund - Large Collaborative Grant (OFLCG18May-0028) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC). N.F.G. acknowledges funding support from the NMRC Transition Award (NMRC/TA/0051/2016) and the NMRC Centre Grant (TETRAD 2). B.H.S.W. and Z.S.P. were provided with PhD fellowship by HealthTech NTU and Lee Kong Chian School of Medicine, Nanyang Technological University Singapore