Acquired Resistance Mechanisms in Immune Checkpoint Inhibition

Immune checkpoint inhibitors have revolutionised cancer treatment by unleashing cytotoxic T-cell responses against tumours, yet a significant subset of patients who initially benefit will ultimately develop acquired resistance. Mechanisms of resistance may arise from tumour-intrinsic changes, including loss or alteration of antigen presentation machinery, depletion of neoantigens through immunoediting, mutations in interferon γ (IFNγ)–JAK signalling pathways and epigenetic reprogramming that silences key immune genes. Tumour cells can also upregulate alternative inhibitory checkpoints such as TIM-3, LAG-3 or TIGIT to evade sustained T-cell attack. In parallel, the evolving tumour microenvironment increasingly favours immune escape through recruitment of regulatory T cells, myeloid-derived suppressor cells and polarised macrophages, and by producing immunosuppressive cytokines and metabolites that inhibit effector lymphocytes. Recent work has even revealed novel cell-in-cell structures that shield tumour cells from immune-mediated killing. Clinically, these biological phenomena manifest as oligo-progression in one or few sites, or systemic relapse, with organ-specific patterns that can guide subsequent local or systemic interventions. A deeper understanding of these interconnected pathways is essential to designing rational combination strategies—ranging from dual checkpoint blockade to epigenetic modifiers, STING agonists or targeted delivery systems—that may prevent or overcome acquired resistance and extend meaningful survival across diverse tumour types.

Research from Nature Portfolio

Studies in preclinical lung adenocarcinoma models have shown that tumours escaping PD-1 blockade frequently exhibit adaptive upregulation of alternative checkpoints such as TIM-3 on T cells bound by PD-1 antibodies, and that sequential targeting of TIM-3 can restore antitumour immunity following PD-1 failure. Clinical analyses of non-small-cell lung cancer patients who experienced durable responses to PD-1 or PD-L1 inhibitors revealed a predominance of oligo-progression—often limited to lymph nodes or a single organ—with longer post-progression survival in cases of extrathoracic relapse. These patterns underscore the potential benefit of local therapies or continuation of checkpoint inhibitors beyond initial progression in select patients.

Acquired Resistance Mechanisms in Immune Checkpoint Inhibition publication trend

The graph below shows the total number of articles in acquired resistance mechanisms in immune checkpoint inhibition across all publications each year (not limited to Nature Index journals).

Technical terms

Neoantigen: A novel peptide generated by tumour-specific mutations that can be recognised by T cells.

Antigen presentation: The display of peptide–major histocompatibility complex complexes on cell surfaces to engage T-cell receptors.

Interferon γ (IFNγ) signalling: A cytokine-driven pathway essential for antitumour immunity but implicated in resistance when deregulated.

Alternative immune checkpoint: Inhibitory receptor, such as TIM-3 or LAG-3, that tumour cells exploit to dampen T-cell activity.

Tumour microenvironment (TME): The network of stromal cells, immune cells and molecules surrounding tumour cells that influences therapeutic outcome.

Oligoprogression: Limited disease progression at a small number of lesions following an initial favourable response to therapy.

Epigenetic modification: Heritable changes in gene expression without alteration of the DNA sequence, often by DNA methylation or histone modification.

Cell-in-cell formation: A transient structure wherein one tumour cell engulfs another, conferring protection against immune-mediated killing.

References

1. Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer. Cancer Cell (2024).
2. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nature Communications (2016).
3. Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors. Cancers (2020).
4. Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy. eLife (2022).
5. Overcoming acquired resistance to cancer immune checkpoint therapy: potential strategies based on molecular mechanisms. Cell & Bioscience (2023).