71 Scientists have identified a protein that plays a crucial role in cancer cells’ ability to resist chemotherapy and radiotherapy, raising hopes for more effective treatments in the future. The protein, known as glucose-regulated protein 78 (GRP78), is found at high levels in many cancers and has been shown to aid tumour survival by preventing cell death and enabling cancer cells to evade treatment. The findings were published in the journal Medical Oncology. Research has revealed that GRP78 supports cancer cells in multiple ways, including promoting cancer stem cell properties, inhibiting apoptosis – the process of programmed cell death – and helping tumours adapt to stressful conditions. By influencing key cellular pathways, GRP78 can allow cancer cells to repair DNA damage, resist oxidative stress, and modify the tumour microenvironment to become more favourable for survival. This ability to confer resistance to radiotherapy and chemotherapy makes it a significant barrier to successful cancer treatment. One of the primary mechanisms through which GRP78 aids in treatment resistance is by protecting cancer stem cells, a subpopulation of cells within tumours that are particularly aggressive and difficult to eliminate. These cells are often responsible for cancer relapse following treatment. Studies have shown that reducing GRP78 levels in these cells can increase their sensitivity to chemotherapy, suggesting that targeting GRP78 may improve treatment outcomes. Another critical function of GRP78 is its involvement in autophagy, a process that helps cancer cells survive under adverse conditions by breaking down and recycling cellular components. This mechanism allows tumours to withstand the effects of anti-cancer drugs and radiotherapy, making them harder to destroy. Additionally, GRP78 has been linked to immune system evasion, enabling tumours to suppress immune responses that would otherwise help eliminate cancer cells. Given its pivotal role in cancer progression and treatment resistance, GRP78 has emerged as a target for new therapies. Several drugs designed to block or reduce GRP78 activity are currently being investigated. Among them is BOLD-100, a drug that has reached Phase II clinical trials. BOLD-100 works by reducing GRP78 levels, leading to increased sensitivity of cancer cells to chemotherapy. Early trials have shown promising results, particularly in combination with existing chemotherapy drugs, but further research is needed to determine its full potential. Another drug, PAT-SM6, was initially considered a promising anti-GRP78 therapy, but its clinical development has stalled due to limited efficacy in trials. Similarly, NKP-1339, a ruthenium-based drug that targets GRP78, showed some potential in early trials but has yet to progress beyond Phase I clinical testing. The mixed results highlight the complexity of targeting GRP78 and the need for more refined approaches. Scientists are also exploring novel delivery methods to minimise potential side effects. Since GRP78 is present in some normal cells, there is concern that treatments targeting this protein could harm healthy tissues. One approach under investigation is the use of nanoparticles to deliver GRP78 inhibitors directly to cancer cells while sparing healthy ones. The growing understanding of GRP78’s role in cancer treatment resistance underscores the importance of continued research. If scientists can develop effective ways to block this protein, it could lead to major advancements in cancer therapy, offering new hope for patients facing treatment-resistant tumours.