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During photothermal therapy (PTT), hyperthermia up to 50 °C is required for efficient induction of tumor cell death. Additional increases in temperature can lead to severe damage to adjacent tissues. Conversely, insufficient heating of deep‐seated tumor tissues results in tumor recurrence. Sensitization of tumor cells to PTT may solve this problem. Stress granules (SGs) function in integration of various internal and external stresses to regulate cell viability. However, the role of SGs in PTT is currently unknown. Here, with black phosphorus (BP) nanosheets as photothermal agents, it is found that SGs are induced in tumor by PTT through eukaryotic initiation factor 2α‐dependent pathway and participate in tumor resistance to PTT. To modulate SG formation in tumor, a BP hydrogel is prepared for tumor‐specific delivery and near‐infrared (NIR) light‐controlled release of the SG inhibitor Emetine. Upon NIR‐light irradiation, photothermal conversion of BP nanosheets enables PTT of tumor. Meanwhile, light‐controlled release of Emetine in tumor tissues effectively inhibits PTT‐induced SG formation and sensitizes tumor to PTT, resulting in enhanced tumor inhibition. These results reveal the role of SGs in PTT and present a novel strategy for tumor sensitization to enhance the therapeutic efficacy and reduce the side effects of PTT. [ABSTRACT FROM AUTHOR]

Nanomaterials‐based photothermal therapy (PTT) could efficiently eliminate cancer cells in a noninvasive manner. However, nanoscale photosensitizers still suffer from several drawbacks, limiting them from being an ideal PTT approach against cancer. These include unfavorable biodistribution and poor retention in tumor tissue. In this study, acid‐activatable smart self‐assembly of black phosphorous (BP) and polyoxometalates (POM) is carried out to yield POM@BP with prolonged tumor retention and enhanced efficacy of PTT. The as‐rationally designed POM@BP photosensitizers in acidic tumor microenvironments self‐assemble into nanoparticles with larger sizes, remarkably increasing the light absorption ability of BP nanosheets in PTT of cancer. The as‐obtained POM@BP endows prolonged retention and enhances the photothermal response in tumor tissue by smart self‐assembly of BP into larger nanoparticles. In summary, the proposed potent approach for the rational design and tailor photosensitizer for cancer treatment looks very promising for future scientific breakthroughs in nanomedicine. [ABSTRACT FROM AUTHOR]