Cancer research has traditionally emphasized tumor cell–intrinsic drivers of malignancy, yet mounting evidence demonstrates that cancer progression, therapeutic resistance, and metastasis are critically shaped by the tumor microenvironment (TME). Rather than serving as a passive scaffold, the TME constitutes a dynamic and heterogeneous ecosystem composed of immune, stromal, and vascular elements that actively regulate tumor behavior. Despite strong biological rationale, therapeutic strategies targeting the TME have produced inconsistent clinical outcomes, with many approaches failing to translate durable benefit to patients. In this review, we critically examine why TME-targeted therapies have underperformed in clinical settings. We synthesize recent literature to highlight key challenges, including cellular and spatial heterogeneity, adaptive resistance mechanisms, unintended depletion of tumor-restraining components, immune-related toxicities, and limitations of current preclinical and clinical trial designs. We argue that non-selective ablation of microenvironmental compartments frequently disrupts protective regulatory functions, thereby undermining therapeutic precision. We further discuss how emerging technologies such as single-cell and spatial multi-omics are reshaping our understanding of TME complexity and enabling more refined therapeutic strategies. Rather than advocating for broad elimination of microenvironmental components, we emphasize the need for selective modulation, functional reprogramming, and biomarker-guided patient stratification. By reframing the TME not simply as a therapeutic target but as a dynamic system requiring precision intervention, this review provides a critical perspective on past failures and outlines rational directions for the next generation of microenvironment-informed cancer therapies.

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