Turning Cold into Hot: Firing up the Tumor Microenvironment

Understanding the composition, proportion, activation, or functional states of immune infiltrates within the TME are critical for both diagnosis and therapeutic intervention. There remains the need to develop novel technologies to explore the primary and metastatic TME ex vivo or in situ. ‘Hot’ tumors are characterized by the accumulation of proinflammatory cytokines and T cell infiltration, and have a better response rate to ICB treatment. Alterations of endogenous innate immunity sensing within tumor cells could transduce the signals of cell transformation and malignancy to the TME and consequently regulate antitumor immunity. Dysregulated cellular signaling and metabolism within tumor cells would affect the TME and response to immunotherapy. Cancers develop within complex tissue environments consisting of diverse innate and adaptive immune cells, along with stromal cells, vascular networks, and many other cellular and noncellular components. The high heterogeneity within the tumor microenvironment (TME) remains a key obstacle in understanding and treating cancer. Understanding the dynamic functional interplay within this intricate ecosystem will provide important insights into the design of effective combinatorial strategies against cancer. Here, we present recent technical advances to explore the complexity of the TME. Then, we discuss how innate immune sensing machinery, genetic alterations of oncogenic signaling, cellular metabolism, and epigenetic factors are involved in modulating the TME. Finally, we summarize the potential strategies to boost antitumor immunity by therapeutically exploiting the TME. Cancers develop within complex tissue environments consisting of diverse innate and adaptive immune cells, along with stromal cells, vascular networks, and many other cellular and noncellular components. The high heterogeneity within the tumor microenvironment (TME) remains a key obstacle in understanding and treating cancer. Understanding the dynamic functional interplay within this intricate ecosystem will provide important insights into the design of effective combinatorial strategies against cancer. Here, we present recent technical advances to explore the complexity of the TME. Then, we discuss how innate immune sensing machinery, genetic alterations of oncogenic signaling, cellular metabolism, and epigenetic factors are involved in modulating the TME. Finally, we summarize the potential strategies to boost antitumor immunity by therapeutically exploiting the TME. certain chromatin modifications that can modulate gene expression without altering DNA coding sequence. surveillance from both innate and adaptive immunity to recognize and monitor tumor growth. the ability of a foreign substance to confer a certain level of immunity to the host. spreading of primary tumor in adjacent or distant organ/tissue. an intricate ecosystem that is highly heterogenous and dynamic, which consists of multiple non-cellular and cellular components including tumor cells, stromal cells, vascular structure and diverse innate and adaptive immune cells.