Table 3

ICD induction by targeted and nanoparticle-incorporated photosensitizers (PS) of the third generation

PS	Subcellular localization of PS	Cell line	Markers of cell death and cell death types	DAMPs expression	Immunogenicity of cancer cell in vitro	Immunogenicity of cancer cells in vivo	References
Cetuximab-IR700	Bind to HER1-overexpressed on the plasma membrane of cancer cells	A431 human epidermoid carcinoma	N/D	Surface exposure of HSP70, HSP90 and CRT; release of ATP and HMGB1	Phenotypic maturation of DCs (CD80^high, CD86^high, MHC II^high), production of IL-12	NIR-PIT-treated A431cells growing in homozygotic athymic nude mice: CD86⁺ population of DCs, ↑ CD11c, CD205 and MHC II positive cells	95
Chlorin-based nanoscale metal-organic framework	N/D	CT26 murine colorectal carcinoma	Apoptosis and necrosis (flow cytometry: PtdSer and PI)	Surface exposure of CRT	N/D	N/D	96
Chlorin-based nanoscale metal-organic framework	N/D	MC38 murine colon adenocarcinoma	Apoptosis and necrosis (flow cytometry: PtdSer exposure and PI)	Surface exposure of CRT	N/D	PDT+IDO inhibitor-treated MC38 tumors growing in C57BL/6 mice: ↑ tumor-infiltrating neutrophils, B cells, CD45⁺ leukocytes, CD4⁺ T cells, NK cells and CD8⁺ T cells	140
Core-shell nanoscale coordination polymer conjugated with pyropheophorbide lipid (NCP@pyrolipid)	N/D	CT26 murine colorectal carcinoma, MC38 murine colon adenocarcinoma	Apoptosis and necrosis (flow cytometry: PtdSer exposure and PI)	Surface exposure of CRT on CT26 cells	N/D	Prophylactic vaccination model using PDT-treated CT26 cells in BALB/c mice: ↑ TNF-α, IL-6 and IFN-γ in serum. PDT and PD-L1 blockade-treated MC38 tumors growing in C57BL/6 mice: ↑ antigen-specific IFN- γ-producing T cells in splenocytes, ↑ infiltrating CD8⁺ T cells in primary and distant tumors, ↑ infiltrating CD45⁺ and CD4⁺ T cells in distant tumors	97
Zn-pyrophosphate nanoparticles loaded with the PS pyrolipid (ZnP@pyro)	N/D	4T1, TUBO murine mammary carcinoma	Apoptosis and/or necrosis (flow cytometry, confocal imaging: PtdSer exposure and PI)	Surface exposure of CRT (in vitro and in vivo)	N/D	PDT-treated 4T1 tumors growing in orthotopic mice: ↑ TNF-α, IL-6 and IFN-γ in serum. PDT+anti-PD-L1-treated TUBO tumors growing in syngeneic mice: ↑ CD8⁺, CD45⁺ and CD4⁺ T cells and B cells	98
Graphene oxide conjugated with the HK peptide, coated with a PS HPPH (GO(HPPH)-PEG-HK)	N/D	4T1 murine mammary carcinoma	Necrosis (flow cytometry: PtdSer exposure and 7-AAD)	N/D	Phenotypic maturation of DCs (CD80^high, CD86 ^high)	PDT-treated 4T1 cells growing in BALB/c mice: ↑ CD40 and CD70, maturation markers of DCs, ↑ IFN-γ in serum, ↑ CD8⁺ T cells. Prophylactic vaccination model using PDT-treated 4T1 necrotic cells in BALB/c mice	99
Core-shell gold nanocage coated with manganese dioxide (AuNC@MnO2)	N/D	4T1 murine mammary carcinoma	Apoptosis (flow cytometry: PtdSer exposure)	Surface exposure of CRT (in vitro and in vivo), release of ATP and HMGB1	Phenotypic maturation of DCs (CD83 ^high, CD86 ^high), production of IL-12	PDT-treated 4T1 cells growing in BALB/c mice: ↑ CD11c⁺CD86⁺ and CD11c⁺CD83⁺ DCs in tumors, ↑ NK cells in tumors and CD8⁺ and CD4⁺ in both tumors and TDLNs, ↓ intratumoral T_regs	106
Hybrid protein oxygen nanocarrier with chlorin e6 encapsulated (C@HPOC).	N/D	4T1 murine mammary carcinoma	N/D	Surface exposure of CRT (in vitro and in vivo); release of HMGB1 and ATP	Phenotypic maturation of DCs (surface upregulation of CD86 and MHC II)	PDT-treated 4T1 tumor-bearing BALB/c mice: tumor inﬁltration of NK cells, CD8⁺ and CD4⁺ T cells, ↑ DC maturation, ↑ activated NK cells, CD8⁺ and CD4⁺ T cells both in tumors and TDLNs	109
Hyaluronidase-responsive size-reducible biomimetic nanoparticles, coated with RBC membrane and loaded with PS pheophorbide A, ROS-responsive paclitaxel dimer prodrug (PXTK) and anti-PD-L1 peptide dPPA (pPP-mCAuNCs@HA)	HA bound to CD44 overexpressed on 4T1 cells	4T1 murine mammary carcinoma	N/D	Surface exposure of CRT; release of HMGB1	N/D	Treatment of 4T1 tumor-bearing BALB/c mice with pPP-mCAuNCs@HA+laser: intratumoral inﬁltration of CD8⁺ and CD4⁺T cells, proliferation of CD8⁺ T cells, ↑ NK cells and CD4⁺ T cells in blood circulation, ↑ TNF-α and IL-12 in serum	141
Redox-activated porphyrin-based liposome remote-loaded with indoximod (IND@RAL)	RAL co-localized in lysosomes, then PS was released and translocated to the whole cytoplasm, including mitochondria	4T1 murine mammary carcinoma	Apoptosis (flow cytometry: positive staining to annexin V-FITC)	Surface exposure of CRT (in vitro and in vivo); release of ATP and HMGB1	N/D	IND@RAL-PDT treated 4T1 cells growing in BALB/c mice: inﬁltration of cytotoxic T lymphocyte, ↑ CD3⁺CD8⁺ leukocytes but not CD3⁺CD4⁺ T cells in the tumor tissues, ↑ cytotoxic T cell and ↓ T_regs in the peripheral blood	142
Nanosystem consists of ER-targeting pardaxin (FAL) peptides modiﬁed, indocyanine green (ICG)-conjugated hollow gold nanospheres (FAL-ICG-HAuNS), together with an oxygen-delivering hemoglobin liposome (FAL-Hb lipo)	ER	CT26 murine colon carcinoma, B16 murine melanoma	Apoptosis in CT26 cells (WB: caspase-3 cleavage and CHOP expression)	Surface exposure of CRT in CT26 and B16 cells	N/D	PDT+PTT-treated CT26 cells growing in BALB/c mice: DC maturation in lymph nodes, ↑ MHC I and MHC II on tumor surface, ↑ CD8⁺ T cells, ↓ T_regs in spleen tissue, ↑ TNF-α and IFN-γ levels in blood. PDT+PTT-treated B16 cells growing in BALB/c mice: ↑ CD11c⁺/CD80⁺/CD86⁺ DCs in lymph nodes, ↑ CD4⁺ T cells and CD8⁺ T cells in spleen tissue, inﬁltration of CD3⁺ T cells, ↑ CD8⁺ T cells and ↓ T_regs in tumor tissue, ↑ IL6, TNF-α, IFN-γ and ↓ IL-10 levels in tumor	45
The covering macrophage membrane with shape changeable carriers (chlorin e6/BR-FFVLK-PEG) co-incorporated with paclitaxel (PTX) and indoximod (IND) in the core (I-P@NPs@M)	N/D	4T1 murine mammary carcinoma	Apoptosis (flow cytometry: positive staining to annexin V-FITC)	Surface exposure of CRT and HMGB1; release of ATP and HMGB1 (in vitro); expression of HMGB1 and CRT (in vivo)	N/D	Therapeutic and prophylactic vaccination model using PDT-treated 4T1 cells in BALB/c mice: ↑ CTLs and ↓ T_regs in tumors, ↑ circulating CD4⁺, CTLs and NKs, ↑ IL-2, IL-12, IFN-γ and TNF-α levels, ↓ IL-10 level, ↑ mature DCs in spleen (CD11c⁺ CD80^high, CD11c⁺ CD83^high or CD11c⁺ CD86^high)	143
pH-responsive nanovesicles self-assembled from block copolymer polyethylene glycol b-cationic polypeptide co-encapsulated with a PS HPPH and indoximod (pRNVs/HPPH/IND)	Endosome/lysosome then drug released in cytoplasm and ER	B16F10 murine melanoma	Apoptosis (flow cytometry: PtdSer exposure)	Surface exposure of CRT	N/D	pRNVs/HPPH/IND-PDT treated B16F10 cells growing in C57BL/6 mice: ↑ IL-6 and TNF-α levels in blood, reduction both primary and distant tumor growth by infiltration of CD8⁺ T cells	144
Phase-transition nanoparticles loaded with perﬂuoropentane, indocyanine green and oxaliplatin (OI_NPs)	N/D	ID8 murine ovarian surface epithelium	Apoptosis (flow cytometry: PtdSer exposure)	Surface exposure of CRT; release of ATP; translocation and release of HMGB1	N/D	Prophylactic vaccination model using OI_NPs-PSD treated ID8 cells in C57BL/6 mice; T lymphocytes from the spleens of OI_NPs+PSDT immunized mice were capable of lysing ID8 cells in an E/ T-dependent pattern	145
Janus nanobullets integrating chlorin e6 loaded, disulfide-bridged mesoporous organosilica bodies with magnetic heads, cloaked with breast cancer cell membrane (CM@M-MON@Ce6)	N/D	MCF-7 human ductal carcinoma, 4T1 murine mammary carcinoma	N/D	Surface exposure of CRT; release of HMGB1 (in MCF-7 cells); release of HMGB1 (for 4T1 cells in vivo)	Phenotypic maturation of DCs (CD11c, CD80, CD86)	CM@M-MON@Ce6-magnetic hyperthermia-PDT treated 4T1 tumors growing in BALB/c mice: ↑ IL-6, IFN-γ and TNF-α levels. The ratio of CD8⁺ T cells to CD4⁺ T cells reduced the percentage of T_regs in the tumor	146
The metal–organic framework-based nanoparticles self-assembled from H2TCPP and zirconium ions with hypoxia inducible factor signaling inhibitor (ACF) and immunogenic adjuvant (CpG) loading, and hyaluronic acid coating on the surface (PCN-ACF-CpG@HA)	Hyaluronic acid bind to CD44-overexpressed on the plasma membrane of H22 cancer cells	H22 murine hepatocellular carcinoma	N/D	N/D	Phenotypic maturation of DCs (CD83^high, CD86 ^high, CD317 ^high, MHC II ^high), production of IL-12p70, IFN-γ and TNF-α	PDT-treatment of H22 tumor-bearing BALB/c mice: DC maturation in TDLNs, ↑ IL-12p70, IFN-γ and TNF-α at the tumor site, infiltrating CD8⁺ and CD4⁺ T cells at the tumor site	147
Nanoparticles for targeting mitochondria via co-assembling doxorubicin with triphenylphosphonium-tailored IR780 derivative (T780) along with bovine serum albumin as biomimetic corona (BSA@T780/DOX NPs)	Mitochondria	4T1 murine mammary carcinoma	Apoptosis (flow cytometry: PtdSer exposure)	Surface exposure of CRT; release of HSP70	Proliferation of T cells co-incubated with photo-chemotherapeutic-treated 4T1 cells	Treatment of 4T1 tumor-bearing BALB/c mice with BSA@T780/DOX NPs: ↑ CD4⁺ and CD8⁺ T cells, ↑ ratios of CD8⁺ T cells or CD4⁺ T cells to T_regs in splenic lymphocytes and distant tumors; ↑ CD8⁺CD44⁺CD122⁺ memory T cell ratio in splenic lymphocytes, ↓ T_regs in splenic lymphocytes and distant tumors, ↑ IL-6 and IFN-γ levels in serum	148
Serum albumin-coated boehmite (B; aluminum hydroxide oxide) organic-inorganic scaffold, loaded with chlorin e6, and a honeybee venom melittin (MLT) peptide (Ce6/MLT@SAB)	Cytoplasm (for Ce6/MLT@SA), endosomal/lysosomal distribution for Ce6	4T1 murine mammary carcinoma	Apoptosis/secondary necrosis (flow cytometry: PI)	Surface exposure of CRT; release of ATP	Maturation of BMDCs (upregulation of CD80 and CD86)	Photo-treatment of 4T1 tumor-bearing BALB/c mice with anti-PD-1+Ce6/MLT@SAB: ↑ CD4⁺ and CD8⁺ T cells. No effect on the number of myeloid-derived suppressor cells	149
Polydopamine nanoparticles coated with an upconversion layer of NaGdF4:Yb/Er shell and surface-loaded chlorin e6 (PDA@UCNP-PEG/Ce6)	N/D	4T1 murine mammary carcinoma	Apoptosis (flow cytometry: PtdSer exposure)	Surface exposure of CRT	N/D	Treatment of 4T1 tumor-bearing BALB/c mice with PDT/PTT: DCs maturation in TDNLs (CD80^high, CD86 ^high); ↑ CD4⁺ and CD8⁺ T cells in the spleen; ↑ IL-6, MCP-1, IFN-γ, TNF-α and IL-12p70 levels in serum, but ↓ IL-10 level. Treating 4T1 tumor-bearing BALB/c mice with PDA@UCNP-PEG/Ce6 nanoprobes+PD-1 blockade antibody: ↑ CD8⁺ T cells and IFN-γ level (expressed by CD4 and CD8 cells) but ↓ T_regs in the spleen and lymph node; ↑ macrophages, B cells and effector memory T cells in the spleen; ↑ IL-6 and TNF-α levels in serum	150
Iridium photocatalyst	Mitochondria	A549 human lung carcinoma	Apoptosis (fluorescent microscopy: PtdSer exposure)	Surface exposure of CRT; release of HMGB1	N/D	N/D	151
Liposomes encapsulated in protoporphyrin IX conjugated with NLG919 (IDO inhibitor) (PpIX-NLG@Lipo)	N/D	4T1 murine mammary carcinoma	Apoptosis/secondary necrosis (flow cytometry: PtdSer exposure and PI)	Surface exposure of CRT; release of ATP	N/D	Treatment of 4T1 tumor-bearing BALB/c mice with PpIX-NLG@Lipo-PDT: ↑ CD8⁺ T cells infiltration into distant tumor sites	152
Smart nano-enabled platform, in which IR780 and tirapazamine were coloaded in poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL) (PEG-PCL-IR780-TPZ NPs)	N/D	4T1 murine mammary carcinoma	N/D	Surface exposure of CRT (in vitro and in vivo); release of ATP and HMGB1	BMDCs maturation (surface upregulation of CD83 and CD86), production of IL-12.	Treatment of BALB/c mice with PEG-PCL-IR780-TPZ NPs+laser-treatment of the 4T1 tumors: ↑ CD11c⁺CD86⁺ DCs; inﬁltration of activated CD8⁺ T cells into tumors	153
Light-inducible nanocargo (LINC) (reduction-responsive heterodimer of PS pheophorbide A (PPa)+NLG919 (IDO-1 inhibitor+oxaliplatin). LINC were preirradiated with 671 nm laser to cleave the PEG corona (LINC^L)	N/D	4T1 murine mammary carcinoma	Apoptosis (for 4T1 treated with LINC+laser) (identified by H&E and TUNEL staining)	Surface exposure of CRT and release of ATP and HMGB1 (for both LINC +laser and LINC^L +laser). Surface exposure of CRT and release of HMGB1 of LINC^L/ NC@PPt (NLG919-free)+laser treatment in vivo.	BMDCs maturation (surface upregulation of CD80 and CD86).	Treatment of BALB/c mice bearing 4T1 tumors with LINC^L +laser irradiation: DC maturation in TDLNs, intratumoral secretion of IFN-γ and TNF-α, intratumoral infiltration of CD8⁺ T cells, ↓ intratumoral T_reg, ↑ CD8⁺ T cells to T_regs ratio in the tumor mass, ↑ frequency of T_EM but ↓ frequency of T_CM, ↑ IFN-γ and TNF-α levels in serum. Treatment of 4T1 tumors growing in BALB/c mice with LINC^L+laser inhibited tumor growth after rechallenge with 4T1 cells	154
Cu-5,10,15,20-tetrabenzoatoporphyrin (Cu-TBP) nanoscale metal-organic framework (nMOF)	N/D	B16F10 murine melanoma	Apoptosis (flow cytometry: PtdSer exposure)	Surface exposure of CRT	N/D	Treatment of B16F10 tumor-bearing C57BL/6 mice with Cu-TBP+light irradiation+a-PD-L1: ↑ antigen-specific IFN-γ-producing T cells in spleen; infiltration of CD4⁺ and CD8⁺T cells, ↑ CD45⁺ cells, macrophages and DCs in primary and distant tumors, infiltration of neutrophils to primary tumors. Cu-TBP+light irradiation+a-PD-L1-cured B16F10 tumor-bearing C57BL/6 mice showed resistance to subsequent challenge with B16F10 cells	155
cRGD target liposome with the thymidine conjugate (2 Cl compound) (cRGD-lipo 2 Cl)	cRGD binds to α_vβ₃ integrin receptor, overexpressed on the plasma membrane of cancer cells	MCF-7 human breast cancer, H22 murine hepatocellular carcinoma	N/D	Increased CRT⁺ cell population; release of ATP and HMGB1	N/D	Prophylactic vaccination model using cRGD-lipo 2Cl+UVA activation treated H22 cells in BALB/c mice	144
Core-shell gold nanocage coated with manganese dioxide and hyaluronic acid (AMH)	Hyaluronic acid binds to CD44-overexpressed on the plasma membrane of CT26. WT cancer cells	CT26 WT murine colon carcinoma	Apoptosis (flow cytometry: PtdSer exposure)	Surface exposure of CRT; release of ATP	Phenotypic maturation of DCs (CD83^high, CD86 ^high, MHC II ^high)	N/D	107
PEG-s-s-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(amino(polyethylene glycol) 2000)nanoparticles loaded with TCPP-T^ER (4,4',4'',4'''-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(2-((4methylphenyl)sulfonamido)ethyl)benzamide) (Ds-sP/TCPP-T^ER NPs)	ER	4T1 murine mammary carcinoma	N/D	Surface exposure of CRT; release of HMGB1 (↓ expression of HMGB1 after release); expression of HMGB1 and CRT (in vivo)	Maturation of BMDCs (surface upregulation of CD80 and CD86), production of TNF-α and IL-12p40	PDT-treated 4T1 tumor-bearing mice: ↑ CD8⁺ T cells in the primary and distant tumors, ↑ IL-12P40, TNF-α and INF-γ levels in peripheral blood serum	156

BMDC, bone marrow-derived dendritic cell; CD, cluster of differentiation; CHOP, C/EBP-homologous protein-10; CRT, calreticulin; DC, dendritic cell; ER, endoplasmic reticulum; HAuNS, hollow gold nanospheres; HMGB1, high-mobility group protein box 1; HSP, heat shock protein; ICD, immunogenic cell death; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; N/D, not detected; NK, natural killer; PDT, photodynamic therapy; PI, propidium iodide; PS, photosensitizer; PtdSer, phosphatidylserine; TDLNs, tumor draining lymph nodes; TNF, tumor necrosis factor; T_regs, regulatory T cells; TUNEL, terminal deoxynucleotidyl transferase-mediated nick end labeling analysis; WB, western blot analysis.