ATP‐Responsive Smart Hydrogel Releasing Immune Adjuvant Synchronized with Repeated Chemotherapy or Radiotherapy to Boost Antitumor Immunity

Abstract Certain chemotherapeutics and forms of ionizing radiation can induce immunogenic cell death (ICD). If there simultaneously exist immune adjuvants within the tumor, such antitumor immunity would be further amplified. However, as clinical chemo/radiotherapies are usually repeatedly given at low individual doses, it would be impractical to administrate immune adjuvants into tumors at each dose of chemo/radiotherapies. Thus, a smart hydrogel is developed that releases immune adjuvants in response to repeatedly applied chemo‐/radiotherapies. Herein, alginate is conjugated with an adenosine triphosphate (ATP)‐specific aptamer, which is hybridized with immunoadjuvant CpG oligonucleotide. Upon intratumoral injection, alginate‐based hydrogel is formed in situ. Interestingly, low doses of oxaliplatin or X‐rays, while inducing ICD of tumor cells, could trigger release of ATP, which competitively binds with ATP‐specific aptamer to trigger CpG release. Therefore, the smart hydrogel could release the immune adjuvant synchronized with low‐dose repeated chemo/radiotherapies, achieving remarkable synergistic responses in eliminating established tumors, as well as immune memory to reject re‐challenged tumors. Moreover, repeated radiotherapies assisted by the smart hydrogel could inhibit distant tumor metastases, especially in combination with immune checkpoint blockade. The study presents a conceptually new strategy to boost cancer immunotherapy coherent with repeated low‐dose chemo‐/radiotherapies following a clinically relevant manner.