Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti-PD-1/PD-L1 cancer immunotherapy

Abstract

Chemotherapy, radiotherapy, and immunotherapy represent key tumour treatment strategies. Notably, immune checkpoint inhibitors (ICIs), particularly anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), have shown clinical efficacy in clinical tumour immunotherapy. However, the limited effectiveness of ICIs is evident due to many cancers exhibiting poor responses to this treatment. An emerging avenue involves triggering non-apoptotic regulated cell death (RCD), a significant mechanism driving cancer cell death in diverse cancer treatments. Recent research demonstrates that combining RCD inducers with ICIs significantly enhances their antitumor efficacy across various cancer types. The use of anti-PD-1/PD-L1 immunotherapy activates CD8⁺ T cells, prompting the initiation of novel RCD forms, such as ferroptosis, pyroptosis, and necroptosis. However, the functions and mechanisms of non-apoptotic RCD in anti-PD1/PD-L1 therapy remain insufficiently explored. This review summarises the emerging roles of ferroptosis, pyroptosis, and necroptosis in anti-PD1/PD-L1 immunotherapy. It emphasises the synergy between nanomaterials and PD-1/PD-L1 inhibitors to induce non-apoptotic RCD in different cancer types. Furthermore, targeting cell death signalling pathways in combination with anti-PD1/PD-L1 therapies holds promise as a prospective immunotherapy strategy for tumour treatment.

FIGURE 1

Anti‐PD‐1/PD‐L1 therapy induces non‐apoptotic regulated cell death (RCD) of tumour cells. Anti‐PD1/anti‐PD‐L1 therapy enhances T cell activation and promotes the release of IFNγ, Gzms, and TNF, which can trigger multiple cell death signalling pathways to induce non‐apoptotic RCD, such as ferroptosis, pyroptosis, and necroptosis.

FIGURE 2

Combining anti‐PD1/anti‐PD‐L1 and nanomaterials in ferroptosis‐based cancer therapy. The combination of anti‐PD1/anti‐PD‐L1 and nanomaterials induces the ferroptosis of tumour cells through three pathways: (i) Enhancing the ferroptosis induced by promoting the Fenton reaction, with Fe ions released from nanomaterials. (ii) Nanomaterials (DZ@TFM and DOX‐TAF@FN) promote ferroptosis of tumour cells by inhibiting glutamate‐cystine antiporter system Xc⁻ and downregulating SLC7A11 and GPX4. (iii) GW4869 released from HGF NPs and PFG MPN significantly reduced the generation of tumour‐derived exosome, leading to the enhancement of an antitumor immune response and increasing the level of IFN‐γ cytokine released by T cells to inhibit system Xc⁻ and enhance the ferroptosis.

FIGURE 3

GNPIPP12MA‐induced ferroptosis cooperated with an anti‐PDL1 antibody to reduce AML growth in vivo. (A) Preparation of glutathione‐imprinted nanocomposites loading FTO inhibitor (GNPIPP12MA) and Mechanism of GNPIPP12MA inhibit leukaemia stem cell via targeting N6‐methyladenosine RNA methylation for enhanced anti‐leukaemia immunity. (B) GPX4 activity in Kasumi‐1 and LSC cells treated with 50 μg mL⁻¹ of indicated nanoparticles. (C) Therapeutic regimen of C1498 leukaemia model and WBC counts for indicated groups (n = 6). (D) Representative images of spleen lung with H&E‐stained sections in the indicated groups. Scale bar = 10 μm. (E) Metastatic lesion area of the lung in the indicated groups and the 40‐day survival curve of mice in the indicated groups. (F) Flow cytometry assay of CD8⁺ T cell populations in the indicated groups. Data are mean ± SD; *p <0.05, **p <0.01. n = 6/group. aPDL1: anti‐PDL1. [Adopted from Cao et al. ⁹⁷ ]