DTPs (Drug tolerant persisters) are characterized by low proliferation capacity and are dormant in nature. However, upon withdrawal of drug pressure, the cells can repopulate which may cause recurrence. The nature and survival mechanism of DTPs under high drug pressure are poorly understood. We showed that TNBC (triple negative breast cancer) cell lines (MDA-MB-231 and Hs578T) undergo a DTP state upon treatment of Doxorubicin and Paclitaxel.  These cells show autophagy blockage in the late state characterised by accumulation of P62 and LC3BII. So, prolonged inhibition further by Hydroxychloroquine, or Bafilomycin leads to the death of DTPs aggressively. On the other hand, positive induction by treatment of Rapamycin makes the cell prone to escape from the dormant state and increases the proliferation rate of DTPs. Therefore, the regrown DTPs exhibit an increase in autophagic flux. Again, abundant lysosomal content was found in DTPs. Interestingly, this provides a protective role against the induction of Lysosomal Membrane Permeability and withstands oxidative stress in DTPs. Hereby, the knockdown of LAMP1, a lysosomal membrane protein, enhances oxidative stress more and causes the death of DTPs. Besides, the knockdown of LAMP1 in TNBC cells delays tumor initiation and reduces tumor vascularization in the PDX model. In summary, we identified the critical role of autophagy-lysosomal interplay in the DTPs of TNBC.