Local chemotherapy is a clinically proven strategy in treating malignant brain tumors. Its benefits, however, are largely limited by the rapid release and clearance of therapeutic agents and the inability to penetrate through tumor tissues. We report here on a supramolecular tubustecan (TT) hydrogel as both a therapeutic and drug carrier that enables long-term, sustained drug release and improved tumor tissue penetration. Covalent linkage of a tissue penetrating cyclic peptide to two camptothecin drug units creates a TT prodrug amphiphile that can associate into tubular supramolecular polymers and subsequently form a well-defined sphere-shaped hydrogel after injection into tumor tissues. The hollow nature of the resultant tubular assemblies allows for encapsulation of doxorubicin or curcumin for combination therapy. Our and studies reveal that these dual drug-bearing supramolecular hydrogels enhance tumor retention and penetration, serving as a local therapeutic depot for potent tumor regression, inhibition of tumor metastasis and recurrence, and mitigation of the off-target side effects.