good transmittance through biological tissues as well as high spatial and temporal precision. [3] Recently, the second NIR window (NIR-II, 1000 nm < λ < 1700 nm) has rapidly emerged as a highly promising spectral region for in vivo studies. Compared with the first NIR window (NIR-I, 700 nm < λ < 950 nm), using NIR-II offers numerous merits, including larger penetration depth, lower optical absorption/ scattering from biological specimens, and higher maximum permissible exposure to incident laser, rendering better bioapplication potential. [4][5][6][7][8] The effect of PTT relies on the activation of photosensitizing agents upon NIR irradiation to generate heat for thermal ablation of bio-objects. [9][10][11] Conventional PTT agents, such as organic chromophore molecules, usually requires high radiation energy and high material dose due to their small extinction cross section for light absorption. [2,3,12] Very recently, plasmonic nanomaterials demonstrate distinct advantage as potential PTT agents, owning to their unique optical property of surface plasmon resonance (SPR), which can induce intense localized electric fields to enormously increase light harvesting and favor the excitation of energetic charge carriers. [13][14][15] Thanks to the SPR effect, the absorbed photons can be quickly converted into thermal energy, resulting in instantaneous local high temperature to eliminate lesions, for example, to kill cancer cells. [13][14][15][16] Plasmonic nanohybrids are promising photo energy conversion materials in photoelectronics and biomedicine, due to their unique surface plasmon resonance (SPR). Au and Cu 2−x S x nanostructures with strong SPR in the near-infrared (NIR) spectral region are classic plasmonic systems used to convert NIR photons into heat for photothermal therapy (PTT). The rational design of the Au/Cu 2−x S x nanohybrids is expected to induce better photothermal conversion; however, the construction of such hybrids via wet-chemistry methods with a well-controlled interfacial structure is still challenging. Here, the synthesis of an AuCu Star/Cu 2 −x S x nanohybrid is reported, where the Cu 2−x S x components are selectively grown on the AuCu nanostar tips to form "caps". The spatial formation of the Cu 2−x S x caps on star tips is mainly governed by surfactant concentration, tip curvature, and experimental manipulation. The nanohybrids show low cytotoxicity and superior photothermal conversion efficiency, enabling robust PTT to kill cancer cells in the second NIR window. Numerical simulation reveals that the coupling of Cu 2−x S x on nanostar tips generates strong interfacial electric field, improving photothermal conversion. Moreover, the spatial separation structure favors the continuous flow of hot charge carriers to produce active radicals, further promoting the tumor treatment effect.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/smll.202103174.