Apoptotic tumor cells induced by subtherapeutic doses of chemotherapeutics, radiotherapy, or photodynamic therapy could release tumor associated antigens (TAA), damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines to trigger antitumor immune response, which called ICD [
77]. ICD-inducing modalities can effectively provoke specific T cell responses while killing tumors, and eventually transform a “cold” TME to an immunogenic, “hot” TME [
78].
The application of the nanomaterials endows ICD inducers with superior antitumor activity. Apart from being a synergist of ICD to improve penetration and hypoxia microenvironment as above-mentioned, nanoparticles have several unique advantages in inducing ICD. First, aggregation in tumor site is necessary for ICD inducers. Integrated mesoporous silica nanoparticles armed with classical ICD inductors doxorubicin (DOX), named DOX@HIMSNs, initiated an anti-tumor immune response characterized by DC maturation and antitumor cytokines release [
79]. Second, nanotechnology allows ICD inducers to release in a predictable and designable manner. DOX@HIMSNs has been confirmed to mostly accumulate in tumor tissue and controllably release DOX in acidic microenvironment with high concentration of GSH with the help of integrating a pH and GSH dual stimulated rotaxane [
79]. Third, nanoparticles could effectively induce ICD while reducing their side effect. NPs can selectively deliver photosensitizers to tumors with minimize damage to normal tissues by spatially controlled light irradiation [
78]. Fourth, co-loading multi-components on nanoparticles could significantly improve ICD and anti-tumor effect. Sen et al. engineered a redox-active Au(I) bis-N-heterocyclic carbine (Au(I) bis-NHC) that realized the double effect combining TrxR2 inhibition (damaging biological antioxidants) with increased oxidative stress [
80]. The combination of photodynamic therapy with oxygen therapy based on C@HPOC showed enhanced specific CD8
+ T cell response and abscopal effect [
66]. Fifth, the development of nanoparticles broadens the selection range of ICD inducers. Classical metallic ICD inducer oxaliplatin failed to induce ICD in non-small cell lung cancer (NSCLC) [
81]. An ER-targeting iridium(III) complex, armed with an N,N-bis(2-chloroethyl)-azane derivate, significantly triggered endoplasmic reticulum stress and increased reactive oxygen species by targeting endoplasmic reticulum, resulting in antitumor CD8
+ T cell response and Foxp3
+ T cell depletion, successfully suppling the selection of ICD inducers for NSCLC [
82]. At last, nanoparticles can be used as a synergist of ICD inducers. Min et al. engineered Antigen-capturing NPs (AC-NPs) could play a good synergy with radiotherapy by capturing TAAs released after radiation with different surface chemistry and transport them to APCs [
83].