Keyword: Cancer Resistance

ABSTRACT: Prostate cancer still remains one of the most common cancers in men worldwide, and it is a great therapeutic challenge, especially in the field of immunotherapeutics. The tumour microenvironment (TME) is immunologically “cold” in prostate cancer, and influenced by intrinsic molecular characteristics of the disease such as androgen receptor (AR) signalling, PTEN loss, and lineage plasticity towards neuroendocrine prostate cancer (NEPC). Together, these aspects inhibit antigen presentation, block the entry of cytotoxic T cells and help to establish spatially organised immunosuppressive niches, providing a rational explanation for the clinical variability and partial efficacy of immune-based therapies.
Traditional bulk genomic approaches have provided important insights into tumour biology but are unable to capture the cellular and spatial complexity of tumour–immune interactions. These developments have been spurred by recent advancements in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, which allow to detect individual cell subpopulations within intact tumour tissues, such as exhausted T cells co-expressing PD-1, TIM-3, LAG-3 and TIGIT, immunosuppressive SPP1+ macrophages and various cancer-associated fibroblast subpopulations. These technologies have identified specific immune exclusion sites, stromal–epithelial immune silencing barriers, and therapeutic resistance and immune evasion regulatory programs in the context of prostate cancer specifically.
However, there are still many technical challenges that need to be overcome, such as the lack of patient samples and their demographic diversity, data integration, lack of spatial characterisation of bone metastases and difficulties in clinical translation. Comprehensive multi-omics atlases, AI-driven spatial pattern recognition, functional validation of potential targets and prospective clinical trials based on biomarkers are all important areas for future research. They show significant potential for the creation of better, personalized immunotherapeutic treatment for prostate cancer.

ABSTRACT: Spatial tumour heterogeneity, which denotes the changes in cellular and molecular attributes across distinct locations within a tumour, significantly influences cancer diagnosis and treatment resistance. The heterogeneity of tumour cells inside a singular mass facilitates tumour development, metastasis, and the ineffectiveness of standard therapy. Comprehending the geographical distribution of tumour cells is crucial for formulating more efficient treatment regimens. Diverse methodologies are employed to investigate spatial heterogeneity, encompassing modern imaging techniques such as MRI, PET, and multiplexed imaging, alongside omics approaches including genomes, transcriptomics, and proteomics. These instruments offer insights into the tumour microenvironment and facilitate the identification of resistant subpopulations. The amalgamation of imaging and genomic data via radiogenomics has emerged as a viable methodology, providing an extensive perspective on the spatial and molecular intricacies of tumours. Principal findings reveal that spatial heterogeneity fosters medication resistance by establishing microenvironments characterised by varying oxygen levels, immunological infiltration, and genetic alterations, hence complicating the efficacy of monotherapy strategies. Hypoxic environments and immunological evasion significantly contribute to treatment resistance. Addressing geographical heterogeneity has the potential to enhance cancer treatments. By analysing the molecular and geographical characteristics of tumours, physicians can customise therapies more efficiently, minimising resistance and improving therapeutic results. This methodology signifies a vital advancement in precision medicine, providing more individualised and efficacious cancer therapies in the future.