Therapies such as photodynamic therapy and radiotherapy, are highly dependent on oxygen to generate reactive oxygen species to kill cancer cells. However, the hypoxic environment in the tumor significantly reduces the therapeutic efficacy. Here, thermosensitive lipid nanoparticles are fabricated to deliver a polymerization initiator, which can generate free radicals in an oxygen-independent manner. Indocyanine green is co-encapsulated in the nanoparticles to generate heat upon laser irradiation. Once the temperature is over the melting point of the lipid nanoparticles, the initiator will be released and decomposed to generate free radicals. The free radicals produced in this way demonstrate pronounced anticancer effects in both normoxic and hypoxic environment, holding a great potential to increase the therapeutic effect in clinic.