Photothermal therapy (PTT) and photocatalytic therapy using near-infrared (NIR) laser radiation, which provide high specificity and efficiency, have gained extensive attention as noninvasive treatments for tumor destruction. PTT uses photo-absorbers with high photothermal conversion efficiency to convert light into heat and kill cancer cells via an increase in temperature. PTT requires temperatures over 50 °C to effectively destroy cancer cells. [2] Although such high temperatures may also cause thermal damage to healthy neighboring tissues owing to laser-induced nonspecific heat diffusion, [3] and high temperatures also cause cancer cells to release intracellular molecules that promote immunosuppression, which allows tumor immune escape, metastasis, invasion, and so on, [4] PTT is still an efficient method for obliterating cancer cells thoroughly. However, PTT is combined with other therapeutic approaches could achieve better therapeutic effects.As a novel photo-activated treatment, catalytic medicine has attracted increased attention in recent years for the management of many diseases. This technique allows specific bio-imaging and the administration of versatile therapies through physicochemical effects such as catalytic activity and energy conversion. Photo-activated metal complexes have been suggested to have remarkable potential for cancer treatment. [5][6][7][8] For instance, photocatalysis induces water Nanomaterial-based photothermal and photocatalytic therapies are effective against various types of cancers. However, combining two or more materials is considered necessary to achieve the synergistic anticancer effects of photothermal and photocatalytic therapy, which made the preparation process complicated. Herein, the authors describe simple 2D titanium diselenide (TiSe 2 ) nanosheets (NSs) that can couple photothermal therapy with photocatalytic therapy. The TiSe 2 NSs are prepared using a liquid exfoliation method. They show a layered structure and possess high photothermal conversion efficiency (65.58%) and good biocompatibility. Notably, upon near-infrared irradiation, these NSs exhibit good photocatalytic properties with enhanced reactive oxygen species generation and H 2 O 2 decomposition in vitro. They can also achieve high temperatures, with heat improving their catalytic ability to further amplify oxidative stress and glutathione depletion in cancer cells. Furthermore, molecular mechanism studies reveal that the synergistic effects of photothermal and enhanced photocatalytic therapy can simultaneously lead to apoptosis and necrosis in cancer cells via the HSP90/JAK3/NF-κB/IKB-α/ Caspase-3 pathway. Systemic exploration reveals that the TiSe 2 NSs has an appreciable degradation rate and accumulates passively in tumor tissue, where they facilitate photothermal and photocatalytic effects without obvious toxicity. Their study thus indicates the high potential of biodegradable TiSe 2 NSs in synergistic phototherapy for cancer treatment.