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ECM stiffening is a hallmark of cancer aggressiveness, while survival under substrate detachment also associates with poor prognosis. Mechanisms underlying this, non\u2010linear mechano\u2010response of tumor cells may reveal potential double\u2010hit targets for cancers. Here, an integrin\u2010GSK3\u03b2\u2010FTO\u2010mTOR axis is reported, that can integrate stiffness sensing to ensure both the growth advantage endowed by rigid substrate and cell death resistance under matrix detachment. It is demonstrated that substrate stiffening can activate mTORC1 and elevate mTOR level through integrins and GSK3\u03b2\u2010FTO mediated mRNA m<jats:sup>6<\/jats:sup>A modification, promoting anabolic metabolism. Inhibition of this axis upon ECM detachment enhances autophagy, which in turn conveys resilience of tumor cells to anoikis, as it is demonstrated in human breast ductal carcinoma in situ (DCIS) and mice malignant ascites. 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