BACKGROUND: Stem cell plasticity plays key roles in mammalian organogenesis, tissue homeostasis, and carcinogenesis. Given its tolerance to anti-tumor therapy and its promotion on immunosuppressive microenvironment, cancer cell plasticity is a major contributor to cancer recurrence and metastasis. It is necessary to explore novel avenues to resolve the limitations of current treatments. METHODS: We established stable cancer cell lines harboring all lamin knockdown and then explored the effects of all lamin deficiency on cancer plasticity and tumorigenesis in both cell and subcutaneous mouse models. RESULTS: We found that all lamin knockdown disrupts cancer cell plasticity and impairs tumor progression. The deficiency of all lamin subtypes impaired the stemness and cell cycle transition of cancer cell. Lamin knockdown modulated genomic damage and repair pathways, inhibited mitochondrial function, and triggered cellular senescence. Moreover, lamin knockdown within cancer cell suppressed cancer growth in vivo by enhancing the infiltration and activation of functional T cells. Mechanistically, lamin knockdown reduced the expression of inhibitory immune checkpoints and inflammatory factors in cancer cell via the HIF-1 signaling pathway, which led to the increased sensitivity of cancer cells to chemotherapy. CONCLUSIONS: Overall, our findings characterize the significance of nuclear lamins in cancer cell plasticity and offer an attractive way to improve the effectiveness of anti-cancer therapy.