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A New Approach to an Old Problem
Colorectal cancer remains one of the most challenging malignancies to treat, particularly when tumours develop resistance to immune checkpoint inhibitors. Current therapies rely on monoclonal antibodies to block the interaction between PD-1 on T cells and PD-L1 on tumour cells—a “false handshake” that allows cancer to evade immune attack. While effective for some patients, these antibody treatments are expensive to produce and can be limited by systemic toxicity.
Scientists at Nanyang Technological University, Singapore (NTU Singapore) have taken a fundamentally different approach. Rather than blocking the interaction from outside the cells, they developed microscopic peptide droplets that deliver small interfering RNA (siRNA) to silence the production of PD-1 and PD-L1 at their source. The result, published in Biomaterials, was a 67% reduction in tumour growth in preclinical models—a level comparable to the combination of anti-PD-1 and anti-PD-L1 antibody treatments used as a benchmark.
How the Dual-Droplet System Works
The system uses two separate peptide microdroplet formulations administered together. One, known as siPD-1@THC, carries siRNA against PD-1 and is fitted with anti-CD3 antibodies to target T cells. The second, siPD-L1@HC, delivers siRNA against PD-L1 into colorectal cancer cells. Once inside, the siRNA molecules destroy the genetic instructions needed to produce these checkpoint proteins, effectively disarming the tumour’s immune evasion mechanism from within.
“Our approach works from inside both types of cells,” explained Professor Ali Miserez, senior author of the study. “The siRNA destroys the instructions they need to make these proteins. It is a little like throwing a spanner into a production line, except the disruption is targeted at the recipe for PD-1 or PD-L1”.
Cost Implications and Future Potential
Perhaps the most significant aspect of this research is its economic potential. The researchers estimate that an siRNA-based approach could cost five to ten times less to produce than monoclonal antibody treatments if successfully scaled up. Given the growing burden of cancer care on healthcare systems worldwide, this cost advantage could make immunotherapy accessible to a far broader patient population, particularly in low- and middle-income countries where colorectal cancer incidence is rising.
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The use of microscopic peptide droplets to disrupt the PD-1/PD-L1 “false handshake” is a fascinating alternative to conventional monoclonal antibodies. A reported 67% reduction in colorectal tumour growth is especially promising, though clinical safety and effectiveness in patients will be key next steps.
The use of microscopic peptide droplets to disrupt the PD-1/PD-L1 “false handshake” is a compelling alternative to conventional monoclonal antibodies. A reported 67% reduction in colorectal tumour growth also highlights the potential of this approach for overcoming checkpoint-inhibitor resistance.
The 67% reduction in colorectal tumour growth is especially striking given that the peptide droplets target the PD-1/PD-L1 “false handshake” without relying on costly monoclonal antibodies. It will be interesting to see whether this approach can also overcome resistance to immune checkpoint inhibitors in clinical trials.
The use of microscopic peptide droplets to disrupt the PD-1/PD-L1 “false handshake” is a promising alternative to conventional monoclonal antibodies. A reported 67% reduction in colorectal tumour growth is especially compelling, though the approach will need careful validation in human trials.
The peptide droplets’ ability to disrupt the PD-1/PD-L1 “false handshake” while reducing colorectal tumour growth by 67% is a striking alternative to conventional antibody therapies. It will be interesting to see whether this approach can overcome checkpoint-inhibitor resistance in human clinical studies.
The peptide droplets’ ability to disrupt the PD-1/PD-L1 “false handshake” while reducing colorectal tumour growth by 67% is especially promising. Their potential to offer a more targeted and cost-effective alternative to monoclonal antibodies could help address both treatment resistance and systemic toxicity.
The 67% reduction in colorectal tumour growth is especially promising because these peptide droplets target the PD-1/PD-L1 “false handshake” without relying on costly monoclonal antibodies. It will be interesting to see how well this approach performs in resistant tumours and future clinical studies.