Cancer Immunotherapy Resistance Mechanisms Revealed Through Cellular Stress and Senescence Pathways
Research reveals therapy-induced senescent cancer cells and the integrated stress response pathway play dual roles in cancer immunotherapy resistance. The ATF4-LCN2 axis suppresses anti-tumor immunity by promoting immunosuppressive macrophages, while senescent cells can both enhance and inhibit immune responses. These findings highlight new targets for improving immunotherapy efficacy.
Cancer immunotherapy has markedly improved patient outcomes, particularly when combined with conventional treatments such as chemotherapy, radiotherapy, and targeted therapy, but resistance mechanisms continue to limit efficacy. New research reveals that therapy-induced senescent cancer cells (TISCCs) and the integrated stress response (ISR) pathway play critical roles in promoting immune evasion and therapeutic resistance, representing major challenges for optimizing combination treatment strategies.
Following conventional therapies, a subset of cancer cells can enter a senescent state, ceasing proliferation while remaining metabolically active and persistent within tissues. Such TISCCs significantly influence antitumor immune responses in opposing ways—they can enhance tumor immunogenicity by presenting neoantigens and activating innate immune pathways, but they can also promote T-cell immune evasion and therapeutic resistance, ultimately leading to an immunosuppressive tumor microenvironment. This dual role of TISCCs represents a critical determinant of immunotherapy efficacy, making their precise modulation a major challenge.
Meanwhile, cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs involved in metabolic adaptation, survival and growth. Research shows that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses.
An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours.
The study shows that the ATF4–LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2. Immune checkpoint inhibitors (ICIs) have transformed anti-cancer therapy and become a first-line treatment for several cancers, but many solid tumours do not respond to standard-of-care ICIs. Gaining a better understanding of the mechanisms that underlie immune evasion of ICI-refractory cancers is therefore essential to improve anti-cancer treatments.
Solid tumours progressively reshape their immediate tumour microenvironment, producing features that affect the fitness and characteristics of cells within the TME, such as hypoxia, nutrient scarcity and waste accumulation. In response, cancer cells activate the ISR, an evolutionarily conserved cellular defence system that is triggered by diverse stressors, including misfolded proteins, amino acid starvation and mitochondrial dysfunction. The central driver of ISR activation is the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which reduces global translation while selectively promoting the translation of ATF4.
The ISR and its master transcriptional effector, ATF4, are emerging as key players that respond to several intrinsic stressors during tumorigenesis and contribute to therapy resistance. Although these TME features also profoundly influence anti-tumour immunity, the cancer-cell-extrinsic contribution of the ISR and the ATF4 axis to this process remains mainly unknown. Most studies investigating the role of ATF4 in cancer cells have been performed in vitro or in immunodeficient animals, and consequently its potential role in adaptation and resistance to host immune responses during tumorigenesis has not been defined.
Emerging therapeutic approaches aim to mitigate TISCC-driven immune suppression and improve the overall efficacy of immunotherapy-based combination regimens. The dual regulatory functions of both TISCCs and the ISR-ATF4-LCN2 pathway highlight the complexity of tumor-immune interactions and the need for multi-faceted strategies to overcome immunotherapy resistance.