Introduction
Traditional view of immunogenic cell death
Necroptosis and antitumor immunity
Ferroptosis and antitumor immunity
Pyroptosis and antitumor immunity
Approved drugs that induce necroptosis, ferroptosis, and pyroptosis
Drug name | Daily use | Target | Effect on tumor cell death | References | Effect on antitumor immunity | References |
---|---|---|---|---|---|---|
Sulfasalazine | Anti-inflammatory drug | System Xc- | Ferroptosis induction | [121] | Unknown | |
Glutamate | Nutrient | System Xc- | Ferroptosis induction | [59] | Increased immune suppression | [122] |
Sorafenib | Anticancer drug | System Xc- | Ferroptosis/necroptosis induction | [123] | Null effect on antitumor immunity | [124] |
Cisplatin | Anticancer drug | GSH/GSDME | Ferroptosis/pyroptosis induction | Enhanced antitumor immunity | [126] | |
Statins | Hyperlipemia drug | HMGCR | Ferroptosis induction | [127] | Enhanced antitumor immunity | [128] |
Trigonelline | Nutrient additive | Nrf2 | Ferroptosis induction | [129] | Unknown | |
Artesunate | Antimalarial drug | ROS | Ferroptosis/necroptosis induction | [75] | Enhanced antitumor immunity | |
Shikonin | Thrombocytopenia drug | RIPK1/RIPK3 | Necroptosis induction | [52] | Enhanced antitumor immunity | [133] |
Resibufogenin | Heart failure drug | RIPK3, MLKL | Necroptosis induction | [134] | Unknown | |
5-FU | Anticancer drug | TNF-α/RIPK3 | Necroptosis induction | [135] | Enhanced antitumor immunity | [136] |
Metformin | Anti-diabetes drug | GSDMD | Pyroptosis induction | [137] | Enhanced antitumor immunity | [138] |
Anthocyanin | Nutrient | NLRP3 | Pyroptosis induction | [139] | Enhanced antitumor immunity | [140] |
DHA | Nutrient | GSDMD | Pyroptosis induction | [141] | Enhanced antitumor immunity | [142] |
Paclitaxel | Anticancer drug | GSDME | Pyroptosis induction | [109] | Enhanced antitumor immunity | [143] |
Iron | Nutrient | Ferrous/GSDME | Ferroptosis/necroptosis induction | Enhanced antitumor immunity | [146] | |
Doxorubicin | Anticancer drug | GSH/GSDME2 | Ferroptosis/pyroptosis induction | [147] | Enhanced antitumor immunity | [148] |
Treatment modality | Trial number | Cancer type | Potential nonapoptotic cell death pathway | Main conclusion |
---|---|---|---|---|
Pembrolizumab (anti-PD-L1) + pemetrexed and a platinum-based drug (chemotherapy) | NCT02578680 | Non-small cell lung cancer | Ferroptosis/pyroptosis/necroptosis | In patients with previously untreated metastatic non-squamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. |
Atezolizumab (anti-PD-L1) + bevacizumab plus carboplatin plus paclitaxel (chemotherapy) | NCT02366143 | Non-small cell lung cancer | Ferroptosis/pyroptosis/necroptosis | Improved survival was noted among patients treated with immunotherapy + chemotherapy compared with those only given chemotherapy. |
Atezolizumab (anti-PD-L1) + platinum-based chemotherapy | NCT02367781 | Non-squamous non-small cell lung cancer | Ferroptosis/pyroptosis/necroptosis | Improved survival was noted among patients treated with immunotherapy + chemotherapy compared with those only given chemotherapy. |
Atezolizumab (anti-PD-L1) + platinum (chemotherapy) | NCT02807636 | Locally advanced or metastatic urothelial carcinoma | Ferroptosis/pyroptosis/necroptosis | The use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma. |
Pembrolizumab (anti-PD-L1) + stereotactic body radiotherapy | NCT02492568 | Advanced non-small cell lung cancer | Ferroptosis/necroptosis | The overall response rate is larger in the group with radiotherapy + immunotherapy; however, the positive results were largely influenced by the PD-L1-negative subgroup. |
Pembrolizumab (anti-PD-L1) + docetaxel (chemotherapy) | NCT02574598 | Non-small cell lung cancer | Necroptosis | The combination of pembrolizumab plus docetaxel was well tolerated and substantially improved the ORR and PFS in patients with advanced NSCLC who had previous progression after platinum-based chemotherapy. |
Ipilimumab (anti-CTLA4) + stereotactic ablative radiation therapy | NCT02239900 | Metastatic lesions in the liver or lung | Ferroptosis/necroptosis | This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to the further investigation of combined-modality therapy for metastatic cancers. |