Immune checkpoint inhibitors (ICIs) are a class of molecules that target specific biochemical pathways involved in regulating immune responses. These pathways, known as immune checkpoints, play a critical role in modulating the activity of immune cells, particularly T cells, to prevent inappropriate responses to threats and maintain immune homeostasis. Chimeric antigen receptor T (CAR-T) cells are subject to molecular signals of this type in their surroundings. This is exploited by tumor cells, as they try to change the chemistry of their immediate environment into one which lulls attacking immune cells into a stupor, or towards programmed cell death. However, pairing the administration of CAR-T therapy with signal molecules which counteract those soporific messages from tumor cells may boost the efficacy of CAR-T therapy.

Key checkpoint molecules such as programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) play critical roles in T cell exhaustion and dysfunction within the tumor micro-environment (TME).

Cancer cells often upregulate PD-L1 expression as a mechanism to evade immune surveillance. Monoclonal antibodies targeting either PD-1 or PD-L1 can block this interaction, allowing T cells to recognize and attack cancer cells more effectively. Multiple such therapies have received FDA approval.1

CTLA-4, acts as a negative regulator of T cell activation. Blockade of CTLA-4 with ICIs can enhance T cell activation and proliferation, leading to improved anti-tumor immune responses. Clinical trials have shown that the CTLA-4 inhibitor ipilimumab is effective in treating melanoma, renal cell carcinoma, and colorectal cancer, leading to approval for clinical applications.2

Lymphocyte activation gene 3 (LAG-3) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) are involved in regulating T cell function and can become upregulated in the TME, contributing to T cell exhaustion. While FDA-approved inhibitor options exist for LAG-3, the same is not yet true for TIM-3.3

Going a step further than the application of any of these therapies alone or in combination, research is ongoing which explores the administration of drugs targeting ICIs simultaneously with CAR-T therapy.4 One potential avenue is systemic administration of the drug. There may be a higher risk of side effects with systemic administration, however, as the immune checkpoint which serves an innate immunomodulatory function is interrupted body-wide. Conversely, CAR-T cells can be made to express antibodies themselves against the ICI molecules being manufactured by tumor cells. This way, the effect of the anti-ICI antibodies may be contained to malignant foci without affecting the rest of the body.

While this work is still being developed and refined, the hope is that multiple powerful weapons can eventually be brought to bear simultaneously against the stealthy foe that is cancer. Combination therapies of different kinds are being explored. Some examples include using multiple anti-ICI therapies at once, CAR-T cells targeting multiple antigens at once, employing modified T-cells alongside modified Natural Killer cells, as well as the combination of CAR-T cells with ICI-targeting drugs. These numerous avenues bode well for the future.



  1. Li, Y., Li, F., Jiang, F., Lv, X., Zhang, R., Lu, A., & Zhang, G. (2016). A Mini-Review for Cancer Immunotherapy: Molecular Understanding of PD-1/PD-L1 Pathway & Translational Blockade of Immune Checkpoints. International Journal of Molecular Sciences, 17(7), 1151.
  2. Vaddepally, R.K., Kharel, P., Pandey, R., Garje, R., & Chandra, A.B. (2020). Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence. Cancers, 12(3), 738.
  3. Chocarro, L., Bocanegra, A., Blanco, E., Fernández-Rubio, L., Arasanz, H., Echaide, M., Garnica, M., Ramos, P., Piñeiro-Hermida, S., Vera, R., & et al. (2022). Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor. Cells, 11(15), 2351.
  4. Lv, Y., Luo, X., Xie, Z., Qiu, J., Yang, J., Deng, Y., Long, R., Tang, G., Zhang, C., & Zuo, J. (2024). Prospects and challenges of CAR-T cell therapy combined with ICIs. Frontiers in Oncology, 14.