Stimuli-responsive nanosystems enable highly effective targeting and therapeutic functions, includingchemotherapy and photodynamic therapy (PDT). Traditional PDT alone cannot effectively eradicate thetumor burden; combined with chemotherapy, this combination presents a powerful treatment modalityto modulate the tumor microenvironment (TME). Herein, we report a multi-stimulus responsive alginatenanogel that responds to the change in pH and redox potential in the TME. We coupled oxidized alginatewith 4-mercapto phenylboronic acid and pheophorbide-A (a hydrophobic photosensitizer) and conjugatedwith adipic acid dihydrazide to design the nanogels. Further, we encapsulated doxorubicin, a cytotoxicagent, in the nanogel to enable chemotherapy. The alginate nanogel exhibited the pH-sensitiverelease of both pheophorbide-Aand doxorubicin and simultaneously reduced the redox potential thatenhanced PDT by increasing reactive oxygen species production. Our results demonstrate that themulti-stimuli responsive alginate nanogel enhances toxicity in breast cancer and melanoma.