Cancer immunotherapy holds great promise but faces challenges in efficacy and toxicity. Nanotechnology, particularly using peptide-based drug delivery systems, offers a solution by enabling targeted delivery and controlled release. Herein, we developed a novel peptide-drug conjugate, Ind-GFFYK-SN38, that leverages nanotechnology and a unique tumor-triggered morphology switch for enhanced chemo-immunotherapy. This conjugate self-assembles into nanoparticles capable of efficiently penetrating tumor tissue. Upon encountering tumor-overexpressed esterases, the conjugate releases the chemotherapeutic agent, 7-ethyl-10-hydroxycamptothecin (SN38). Concurrently, this enzymatic cleavage triggers a remarkable morphology switch, transforming the remaining peptide component into anti-metastatic nanofibers. This transition prolongs the retention of the incorporated immune checkpoint inhibitor, Indoximod (Ind), within the tumor microenvironment, leading to enhanced immune activation and potentiated antitumor activity. This innovative nanosphere-to-nanofiber transition offers a promising new strategy for improving the efficacy and safety of cancer chemo-immunotherapy.