By transferring gene encoding CAR, engineered T cell could specifically recognize target antigen on tumor cell with single-chain variable fragment (scFv) domain [
100]. CAR-modified T cell is activated independent of MHC manner and then directly kills tumor cell [
101,
102]. CAR-T therapy has been successfully applied in hematological diseases, but its effect is limited in solid tumors [
103,
104]. It is generally believed that immunosuppressive tumor microenvironment and intratumoral heterogeneity mainly contribute to escape from immune killing by CAR-T cell [
105‐
107]. Smith et al. designed a novel implantable bioactive carrier which could deliver CAR-T cells to the surface of tumors [
108]. Compared with systemic delivery of CAR-modified T cell, delivery by this bioactive carrier significantly enhanced T cell expansion and tumor control [
108]. CAR-T therapy delivered by implanted scaffold prolonged survival time, but the intervention could not completely eliminate tumor in mice [
108]. Under selective pressure, tumor cell with high expression of targeting expression (RAE1) were destroyed while RAE1
low/negative tumor cells survived [
108]. As a result, all mice developed resistance to CAR-T therapy [
108]. Then, the bioactive scaffold was modified with additional STING agonist cyclic di-GMP (cdGMP) [
108]. Co-delivery of cdGMP and CAR-T cells markedly increased the activation of downstream signaling pathway of the TCR/CD3 and circulating tumor-specific T cells [
108]. In mouse pancreatic tumor model, combined delivery of CAR-T cells and cdGMP completely cleared tumor in four of ten mice and significantly prolonged survival time [
108]. To further investigate this combination therapy induced systemic anti-tumor immunity, four mice undergoing complete regression were re-challenged with the intravenous injection of tumor cells [
108]. It was notable that the prior combination treatment inhibited the formation of measurable tumor mass [
108]. We proposed that STING agonist could boost the efficacy of CAR-T-induced in situ cancer vaccine and initiate durable systemic anti-tumor immune response.