Autophagy is a cellular process crucial for maintaining homeostasis by degrading damaged proteins and organelles. It is stimulated in response to stress, recycling nutrients and generating energy for cell survival. In normal endometrium, it suppresses tumorigenesis by preventing toxic accumulation and maintaining cellular homeostasis. It is involved in the cyclic remodelling of the endometrium during the menstrual cycle and contributes to decidualisation for successful pregnancy. Such a process is regulated by various signalling pathways, including PI3K/AKT/mTOR, AMPK/mTOR, and p53. Dysregulation of autophagy has been associated with benign conditions like endometriosis and endometrial hyperplasia but also with malignant neoplasms such as endometrial carcinoma. In fact, it has emerged as a crucial player in endometrial carcinoma biology, exhibiting a dual role in both tumour suppression and tumour promotion, providing nutrients during metabolic stress and allowing cancer cell survival. It also regulates cancer stem cells, metastasis and therapy resistance. Targeting autophagy is therefore a promising therapeutic strategy in endometrial carcinoma and potential for overcoming resistance to standard treatments. The aim of this review is to delve into the intricate details of autophagy’s role in endometrial pathology, exploring its mechanisms, signalling pathways and potential therapeutic implications.

Endometrial carcinoma (EC) is the most common gynaecological malignancy in developed nations, exhibiting significant molecular heterogeneity that impacts prognosis and treatment response, particularly in advanced or recurrent settings. Traditional classification is increasingly supplemented by molecular subtyping (POLE-ultramutated, MSI-high/dMMR, NSMP, p53-mutated/CNH), which provides crucial prognostic information and predicts benefit from immunotherapy. This review summarizes the landscape of predictive biomarkers for immune checkpoint inhibitor (ICI) therapy in EC, emphasizing a new therapeutic scenario for advanced and recurrent EC. Mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), leading to high tumor mutational burden (TMB) and increased neoantigen production, is the most established predictor, resulting in FDA approvals for pembrolizumab and dostarlimab in this subgroup. POLE mutations also confer hypermutation and high immunogenicity, predicting a favorable ICI response. Other biomarkers, including PD-L1 expression and TMB, show variable correlation with response and require further standardization. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs), also influences treatment outcomes. Clinical trials have demonstrated significant survival benefits for ICIs combined with chemotherapy (e.g., dostarlimab/pembrolizumab + carboplatin/paclitaxel) in first-line settings, especially for dMMR/MSI-H EC, and for ICI combinations with targeted agents (e.g., lenvatinib + pembrolizumab) in previously treated patients. Integrating molecular classification and validated biomarkers is essential for optimizing patient selection and developing personalized immunotherapy strategies for EC.