理由：通过缺氧激活荧光探针对微环境进行分子成像已成为肿瘤诊断和图像引导治疗的一种有吸引力的方法。由于肿瘤微环境中的缺氧异质性，其转化应用仍然存在困难，这使得将缺氧图像作为肿瘤分布的可靠指标具有挑战性。方法：我们报告了一种模块化治疗诊断平台，通过光调制信号补偿荧光可视化缺氧，以克服肿瘤异质性，从而作为图像引导手术切除和光动力治疗的诊断工具。具体来说，该平台利用超分子主客体自组装集成了荧光指示剂和光动力调节剂的双模块，作为级联的“与”逻辑门协同工作。首先，肿瘤富集和缺氧区域的特异性荧光开启可以通过肿瘤受体和级联微环境信号作为“AND”门的同时输入来实现。其次，发光荧光模块的图像引导和光动力模块的光介导的内源性耗氧量作为“与”门的双输入协同实现原位光调制信号补偿，表明整个肿瘤中增强的缺氧相关荧光信号的均匀性。结果：在体外和体内分析中，生物相容性平台展示了多种优势，包括双肿瘤靶向能力，以逐步促进特定荧光开启、选择性信号补偿、有利于精确标准化图像引导治疗的成像时间窗口扩展、以及肿瘤谷胱甘肽消耗的功能以提高光动力功效。结论：缺氧激活、图像引导的治疗诊断平台表现出克服肿瘤缺氧异质性的巨大潜力。© 作者。

Rationale: Molecular imaging of microenvironment by hypoxia-activatable fluorescence probes has emerged as an attractive approach to tumor diagnosis and image-guided treatment. Difficulties remain in its translational applications due to hypoxia heterogeneity in tumor microenvironments, making it challenging to image hypoxia as a reliable proxy of tumor distribution. Methods: We report a modularized theranostics platform to fluorescently visualize hypoxia via light-modulated signal compensation to overcome tumor heterogeneity, thereby serving as a diagnostic tool for image-guided surgical resection and photodynamic therapy. Specifically, the platform integrating dual modules of fluorescence indicator and photodynamic moderator using supramolecular host-guest self-assembly, which operates cooperatively as a cascaded "AND" logic gate. First, tumor enrichment and specific fluorescence turn-on in hypoxic regions were accessible via tumor receptors and cascaded microenvironment signals as simultaneous inputs of the "AND" gate. Second, image guidance by a lighted fluorescence module and light-mediated endogenous oxygen consumption of a photodynamic module as dual inputs of "AND" gate collaboratively enabled light-modulated signal compensation in situ, indicating homogeneity of enhanced hypoxia-related fluorescence signals throughout a tumor. Results: In in vitro and in vivo analyses, the biocompatible platform demonstrated several strengths including a capacity for dual tumor targeting to progressively facilitate specific fluorescence turn-on, selective signal compensation, imaging-time window extension conducive to precise normalized image-guided treatment, and the functionality of tumor glutathione depletion to improve photodynamic efficacy. Conclusion: The hypoxia-activatable, image-guided theranostic platform demonstrated excellent potential for overcoming hypoxia heterogeneity in tumors.© The author(s).