<p>Cancer treatment remains in need of novel therapeutic strategies to improve patient outcomes. Cuproptosis, a recently identified form of immunogenic cell death, is recognized for its significant anticancer potential. However, most cuproptosis-based strategies are still in the preclinical stage, and the limited clinical trials conducted thus far have yielded unsatisfactory results. Cancer cells develop resistance to cuproptosis through mechanisms such as metabolic reprogramming or altered signaling pathways. Investigating how to overcome this resistance is therefore crucial for advancing cuproptosis-based therapies. This review summarizes cellular copper homeostasis and its regulation, compares cuproptosis with other immunogenic cell death modalities, and discusses the factors governing cuproptosis sensitivity. From a translational perspective, this review highlights emerging nanomedicine strategies to enhance cuproptosis sensitivity through metabolic vulnerability targeting and pharmacological reversal of resistance mechanisms. Finally, this review envisions the broader therapeutic potential of cuproptosis modulation beyond oncology. These advances may ultimately redefine clinical paradigms, offering hope for meaningful survival extensions and improved quality of life for cancer patients.</p>