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.