Exploring the sarcoma immune landscape

Abstract

Sarcomas are a rare and heterogeneous group of cancers that arise in connective tissues such as bone, muscle, fat, and blood vessels. Despite advances in surgery, radiotherapy, and chemotherapy, treatment outcomes have improved only modestly over the past decade, and many patients experience disease recurrence or develop resistance to conventional therapies. In recent years, immunotherapy has emerged as a promising treatment approach, with immune checkpoint blockade demonstrating clinical activity in selected sarcoma subtypes. However, responses remain highly variable, and the mechanisms underlying sensitivity are not yet fully understood. Increasing evidence indicates that the tumor microenvironment (TME) plays a crucial role in shaping anti-tumor immune responses and determining the efficacy of immunotherapy. Therefore, the aim of this thesis was to characterize the immune landscape of sarcoma subtypes with reported but variable responsiveness to checkpoint blockade, primarily focusing on undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and chordoma. Using state-of-the-art bulk, single-cell, and spatial profiling technologies, this work investigates the cellular composition, spatial organization, and molecular features of the sarcoma TME. Together, the chapters of this thesis provide an in-depth characterization of sarcoma immunobiology and offer insights that may support improved patient stratification and the development of more effective immunotherapeutic strategies for sarcoma patients.