A recent review published in Advanced Cancer Research illustrates that metabolic crosstalk between tumour cells and immune cells shapes immunosuppressive tumour microenvironment in skin cancers, mediating the imbalance between pro-tumour and anti-tumour immunity and limiting durable clinical benefits of immunotherapy.

Systematically dissecting metabolic reprogramming mechanisms and metabolic-targeted interventions provides theoretical support for advancing combinatorial metabolic-immune precision therapy for skin malignancies.

Emerging metabolic intervention strategies, combined with novel analytical technologies and artificial intelligence, create promising avenues to overcome therapeutic bottlenecks in skin cancer treatment.

Skin cancer ranks as the fifth most prevalent malignant tumour worldwide, imposing heavy burdens on global healthcare systems and socioeconomics.

Immunotherapy has revolutionised the treatment landscape of advanced skin cancers and greatly prolongs patient survival; nevertheless, a substantial proportion of patients fail to achieve sustained clinical responses.

Core factors governing anti-tumour immune responses consist of intricate crosstalk between intrinsic tumour characteristics and functional heterogeneity of immune cells within the tumour microenvironment (TME).

Tumour cells remodel energy metabolism via metabolic reprogramming to adapt to hypoxic and nutrient-deficient microenvironments and sustain malignant proliferation.

Such metabolic rewiring not only supplies tumour cells with energy and biosynthetic precursors for survival but also profoundly modulates the proliferation, differentiation and activation of immune cells, ultimately constructing an immunosuppressive TME that fuels tumour progression and metastasis.

Metabolic signatures of immune cells are tightly linked to their differentiation fate, activation status and effector functions.

Meanwhile, immune cells possess remarkable metabolic plasticity, which yields druggable therapeutic targets.

Metabolic-targeted agents can remodel the metabolic milieu of immune cells and hold great translational potential.

These drugs positively boost immune function, elicit robust anti-tumour immune reactions, and lay a theoretical foundation for developing combinatorial therapeutic regimens.

Therefore, systematically elucidating the molecular mechanisms whereby metabolic reprogramming balances pro-tumour and anti-tumour immunity, as well as the capacity of metabolic-targeted drugs to restore patients’ anti-tumour immunity, is an essential prerequisite for translating such therapeutic strategies into clinical practice.

This review systematically outlines metabolic features and associated signalling pathways of tumour and immune cells within the TME, with a focus on how glucose, amino acid and lipid metabolism govern the functions of key immune cell subsets.

It also summarises completed and ongoing clinical trials of metabolic immunotherapy for skin cancers, and thoroughly elaborates how metabolic interventions remodel the TME to favour anti-tumour immunity in skin tumour patients.

Key highlights include:

Metabolic regulation in the tumour microenvironment:

• This review summarises unique metabolic characteristics of common skin cancers, including melanoma and cutaneous squamous cell carcinoma. It also compares distinct metabolic patterns of immune cells under resting and activated states in the tumour microenvironment, providing novel targets for tumour immunotherapy.

Metabolic reprogramming of immune cells:

• Glucose metabolism: tumour cells compete with immune cells for glucose, causing glucose deficiency and lactic acid accumulation. This process regulates immune cell functions via key signalling molecules such as mTOR, HIF-1α, HK2 and PKM2.
• Amino acid metabolism: The metabolism of multiple amino acids, including glutamine and arginine, differentially modulates immune cell activity through mTOR, ATF4, AhR and epigenetic regulatory pathways.
• Lipid metabolism: Lipid metabolism, mediated by CD36, ACC1, FASN, fatty acid oxidation and other key factors, effectively controls immune cell biological functions.

Metabolic interventions for skin cancer treatment:

• This work collects phase I–III clinical trials targeting glucose, amino acid and lipid metabolism in skin cancers, covering single-drug therapy, immunotherapy combination regimens, and non-pharmacological interventions such as exercise and simulated fasting.

Challenges and future perspectives of metabolic therapy:

• Current limitations mainly include inadequate targeting accuracy, treatment-related side effects and poor clinical transformation of preclinical research. Future research will focus on advanced analytical technologies, new metabolic biomarkers and combined intervention strategies.

In conclusion, tumour and immune cells exhibit significant metabolic heterogeneity and plasticity, which jointly shape the immune microenvironment of skin cancer.

This review systematically summarises core metabolic regulatory mechanisms and latest clinical progress of metabolic therapy for skin tumours.

Despite promising preclinical results, the clinical efficacy of metabolic therapy remains unsatisfactory due to targeting defects, adverse reactions and translational barriers.

Emerging technologies will support precise identification of tumour metabolic targets and dynamic metabolic monitoring.

The exploration and verification of metabolic biomarkers are essential for precise metabolic tumour treatment. Importantly, the combination of metabolic intervention and immunotherapy will become a key trend in future skin cancer treatment.

Source: ELSP