Conventional intravenous chemotherapy faces critical challenges, including poor specificity for tumor cells, dose-limiting toxicity, and the emergence of drug resistance, which collectively compromise therapeutic outcomes. Consequently, research has increasingly focused on localized and minimally invasive cancer treatments aimed at achieving high drug concentrations within the tumor while minimizing systemic exposure and adverse effects. In this context, in situ-forming hydrogels administered intratumorally as liquids enable easy injection with minimal damage to surrounding tissues, forming hydrogel depots that promote prolonged residence and sustained release of drugs at the tumor site. Depot formation is driven by endogenous stimuli (body temperature and acidic pH), external triggers (light), or specific chemical cross-linking reactions (click chemistry, Schiff base formation, and enzymatic catalysis). This chapter reviews the predominant strategies for in situ hydrogel formation and highlights promising in vitro and in vivo antitumor activities observed following intratumoral administration of the developed systems. It concludes with observations on clinical translation challenges and future avenues for study.