Cancer has emerged as a major global health threat, with both the incidence and mortality rates rising at an alarming rate. In 2022, the IARC reported approximately 20 million new cancer cases and 9.7 million cancer-related deaths worldwide. Despite significant advancements in cancer treatment, current therapies still face major challenges such as cancer cell resistance and severe side effects caused by high doses of chemotherapeutic agents. DSRHs and MSRHs represent a transformative approach in cancer therapy by responding to two or more stimuli at a time, thereby leveraging the unique TME for targeted drug delivery. These hydrogels respond to external and internal stimuli to enable controlled release of therapeutics, minimizing systemic toxicity while enhancing efficacy. Preclinical studies of these hydrogels have shown promising outcomes in cancer therapy, like sustained drug release, equal or slightly better therapeutic effect compared to clinically approved treatments, and synergistic antitumor activity. Manufacturing complexity, biocompatibility of synthetic polymers, and lack of regulatory guidelines are major barriers for clinical translation of these hydrogels. Despite these barriers, DSRHs and MSRHs show promise in addressing tumor heterogeneity, drug resistance, and off-target effects, emerged as next-generation platforms for cancer treatment.