Metabolic Barriers to Cancer Immunotherapy and the Tumor Microenvironment

Immunotherapy has revolutionized cancer treatment and rejuvenated the field of tumor immunology. Several types of immunotherapy, including adoptive cell transfer (ACT) and immune checkpoint inhibitors (ICIs), have obtained durable clinical responses, but their efficacies vary, and only subsets of cancer patients can benefit from them.

The Role of the Tumor Microenvironment

The immune system plays an essential role in immunosurveillance, as immune cells of the adaptive and innate immune systems infiltrate into the tumor microenvironment (TME) and contribute to the modulation of tumor progression. However, several non-redundant features of the tumour microenvironment facilitate immunosuppression and limit anticancer immune responses. These include:

• Physical barriers to immune infiltration.
• The recruitment of suppressive immune cells.
• The upregulation of ligands on tumour cells that bind to inhibitory receptors on immune cells.

Effective immune responses could either eradicate malignant cells or impair their phenotypes and functions. Nevertheless, cancer cells have evolved multiple mechanisms, such as defects in antigen presentation machinery and the upregulation of negative regulatory pathways, to escape immune surveillance, resulting in the impeded effector function of immune cells.

Metabolic Restrictions on Antitumour T Cells

Recent insights into the importance of the metabolic restrictions imposed by the tumour microenvironment on antitumour T cells have begun to inform immunotherapeutic anticancer strategies. Specifically, metabolic guidance and stress in tumors modulate antigen-presenting cells and affect therapy. Metabolic barriers acting on different phases of immunotherapeutic response include:

• Low glucose levels: Glucose deprivation in the tumour can restrict antitumour T cell activity.
• Extracellular acidosis: A low pH and the interplay between extracellular acidosis and immune cells affect clinical outcomes.
• Lactate: Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions.
• Hypoxia: Hypoxia and the generation of suppressive metabolites facilitate the abrogation of antitumor immune responses.

Emerging Combination Strategies

Therapeutics that target metabolic restrictions have shown promise as combination therapies for different types of cancer. These strategies involve metabolic aspects of the antitumour T cell response in the context of immune checkpoint blockade, adoptive cell therapy and treatment with oncolytic viruses. Systematic interrogation of the TME is feasible and will provide insights into the functional diversities of tumor-infiltrating immune cells, guiding the development of novel immunotherapies for cancer treatment.