Piezo1, a mechanosensitive ion channel, plays a pivotal and multifaceted role in tumor progression, immune evasion, and therapeutic resistance by transducing extracellular mechanical stimuli-such as matrix stiffness and fluid shear stress-into intracellular calcium influx. In tumor cells, Piezo1 promotes proliferation, invasion, and metastasis by activating oncogenic signaling and contributes to an immunosuppressive TME through regulation of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling. In the immune compartment, Piezo1 integrates mechanical cues with metabolic and epigenetic reprogramming to orchestrate the functions of T cells, macrophages, and natural killer (NK) cells. Notably, Piezo1 deficiency impairs TH9 cell differentiation, diminishes T cell cytotoxicity, and enhances the activity of regulatory T cells (Tregs). Furthermore, Piezo1 expression correlates with distinct tumor immune phenotypes, such as "cold tumors," and with responses to immunotherapy, making it a promising predictive biomarker for treatment efficacy. Given its dual regulatory roles in tumor biology and immune modulation, targeting Piezo1-such as through combination with programmed death-1 (PD-1) blockade-offers a potential strategy to reverse immunosuppression and enhance antitumor immunity. This review summarizes emerging insights into Piezo1's role in cancer progression and immune regulation and highlights its translational potential as a novel target in cancer immunotherapy.