73 A protein long known for its role in cellular stress response is now being closely examined as a key player in cancer’s resistance to treatment, potentially paving the way for new targeted therapies. Known as GRP78, this molecule has been found to help cancer cells evade the effects of chemotherapy and radiotherapy, according to an updated review published in Medical Oncology. The paper highlights how GRP78, typically found within the endoplasmic reticulum of cells, becomes overactive in cancerous tissues. This abnormal activity enables tumour cells to survive attacks from treatment, helping them recover and eventually regrow. The review provides a detailed account of how GRP78 supports cancer cell survival, from maintaining stem-like characteristics to suppressing programmed cell death and evading immune system attacks. Researchers found that GRP78 plays a crucial role in enabling cancer stem cells to thrive. These cells are particularly troublesome because they can self-renew and give rise to new tumours even after apparent treatment success. GRP78 helps sustain these cells through its interaction with other proteins and signalling pathways, reinforcing their resistance to chemotherapy and radiation. The study also notes that GRP78 supports the process known as epithelial–mesenchymal transition, which allows tumour cells to become more mobile and invasive. This mobility often leads to metastasis and contributes to a poor prognosis in many cancers. In addition, GRP78 helps regulate autophagy, a mechanism cancer cells use to recycle damaged components and survive under harsh conditions like low oxygen or nutrient deprivation. One of the most concerning findings involves GRP78’s role in shielding tumour cells from DNA damage. Normally, treatments like radiotherapy work by damaging a cell’s DNA beyond repair. GRP78, however, appears to facilitate DNA repair processes, allowing cancer cells to survive what should be lethal blows. Beyond its impact on individual cells, GRP78 also reshapes the tumour microenvironment. It encourages the formation of new blood vessels to nourish tumours and recruits immune-suppressing cells, making it harder for the body to fight back. Some tumours even produce their own antibodies targeting GRP78, triggering signalling cascades that help them grow. Despite these alarming capabilities, researchers are cautiously optimistic. Several experimental drugs are being developed to block GRP78’s functions. BOLD-100, a promising candidate, has shown encouraging results in Phase II clinical trials for chemotherapy-resistant colorectal cancer. Unlike earlier drugs targeting GRP78, BOLD-100 appears to have a longer-lasting effect and better safety profile. Scientists warn, however, that GRP78 is also present in normal cells, where it helps manage cellular stress. As such, therapies must be designed with precision to avoid damaging healthy tissue. Nanoparticle delivery systems that target GRP78 specifically on cancer cells are one approach currently under exploration. As researchers continue to unravel the molecular web that makes GRP78 so central to treatment resistance, the hope is that a more refined understanding will lead to smarter, more effective therapies. For now, GRP78 stands as both a symbol of cancer’s resilience and a potential Achilles’ heel.