The tumor microenvironment's role in the response to immune checkpoint blockade

Abstract

Beyond cancer cells, the tumor microenvironment (TME) includes cells of the innate and adaptive immune systems but also non-immune cells, such as fibroblasts and endothelial cells. Depending on the cues they receive, infiltrating myeloid cells, such as monocytes, macrophages, dendritic cells and neutrophils, perform immune stimulatory or suppressive functions by educating adaptive immune cells, thereby guiding their responses to cancer cells and cancer treatment, such as immune checkpoint blockade (ICB). The increasing understanding that anti-tumor immunity goes beyond T cells with improved functionality, and the unraveling of resistance mechanisms beyond T cell exhaustion, have renewed interest in non-T cell components of the TME to identify novel therapeutic targets and improve ICB responses. Here, we review immune and non-immune cellular components of the TME that regulate adaptive cell responses and their role in ICB response and resistance.

Fig. 1 |. Cancer immunosurveillance and escape mechanisms.

During early stages of cancerous changes in normal cells, continuous immunosurveillance results in identification and elimination of malignant cells through generation of adaptive anti-tumor immune responses. Healthy macrophages mediate phagocytosis and clearance of abnormal cells and present cancer neoantigens to T cells together with DCs. By these mechanisms, the immune system keeps cancer under check even without complete elimination. Evolving escape mechanisms compromise cancer immunosurveillance. Cancer cells escape immunosurveillance by diminishing neoantigen expression and upregulating inhibitory ligands, cytokines, growth factors and DAMPs. Recruitment of MDSCs that are generated from HSPCs during cancer-driven emergency myelopoiesis activated by cancer-produced hematopoietic growth factors, cytokines and DAMPs, and T_reg cells further facilitate cancer immune escape. DCs convert into tolerogenic DCs with compromised ability to process and present tumor neoantigens. Tumor ECs and CAFs structurally modify the microenvironment, supporting the growth of TAMs while impeding the migration and infiltration of adaptive immune cells. Expression of checkpoint inhibitors such as CTLA-4, PD-1, LAG3, TIGIT and TIM-3 in T cells compromises the anti-tumor function of infiltrating T cells. Growth factors: M-CSF, GM-CSF; cytokines: IL-6, IL-1, IL-8; chemokines: CCL2, CCL5, CXCL12, CCL4; DAMPs: DNA, RNA, exosomes, uric acid, ATP, metabolites. ROS, reactive oxygen species.

Fig. 2 |. TECs and CAFs regulate immune cell composition and function in the TME.

a, TECs notably differ from those of nonmalignant tissue counterparts and downregulate the expression of genes involved in T cell recruitment, such as chemokines, T cell activation, such as MHC class I and II, and adhesion and transendothelial migration, such as integrins, and are impaired in pro-inflammatory signaling. b, Five different types of CAFs (depicted in different colors) are localized in the TME, each expressing a unique repertoire of ECM molecules. CAFs secrete CSF1, supporting survival, growth and pro-tumorigenic reprogramming of TAMs. They also inhibit T cell migration into the TME and promote T_reg cell differentiation by producing IL-10 and TGFβ, compromising responses to ICB therapy by both mechanisms. Furthermore, CAFs can recruit MDSCs in the TME by CAF-produced CSF1 and CXCL1 and by secreting CCL2 and recruiting circulating CCR2⁺ monocytes, which become MDSCs in the TME.

Fig. 3 |. Spatial omics as a tool for deciphering TME complexity and enhancing therapeutic strategies.

a, Schematic workflow illustrating the capability of spatial omics to advance our understanding of TME responses and inform precision treatment approaches. For instance, by leveraging paired cohorts such as ICB responders and nonresponders, this approach establishes a functional link between molecular and TME features associated with therapeutic outcomes. Such insights may guide rational design of interventions that more effectively reshape the TME for improved patient responses. b, Overview of key factors for spatial omics applications. Left, balancing probe coverage is crucial for spatial transcriptomics; while high-coverage single-cell analyses enable precise dissection of cell states, this often comes at the expense of whole-tissue insights and may lack the high signal-to-noise ratio that bulk approaches offer. Middle, a well-balanced panel that incorporates both phenotyping and functional targets is optimal for a comprehensive investigation of TME constituents and cellular interactions within. Right, as numerous experimental procedures occur before a tissue sample reaches the laboratory, spatial omics data are highly sensitive to experimental confounders across multiple levels. Ensuring meticulous control over these factors is essential for producing high-quality and interpretable data that reliably capture the TME’s molecular landscape. TMA, tissue microarray. Data cartoon was generated using data from refs. ,.

Fig. 4 |. The immunological landscape in metastatic tumors.

The immune system is involved in all the steps of the metastatic process, including cancer cell migration and intravasation at the primary tumor site, priming of the premetastatic niche and supporting cancer cell growth after seeding at the metastatic site. At the primary tumor, myeloid cells secrete pro-metastatic proteases, which remodel the ECM, allowing cancer cell mobilization and intravasation. Migrating cancer cells are escorted by inflammatory monocytes, which facilitate vascular permeability and recruitment to the premetastatic niche via chemokines and cytokines produced by TRMs and CAFs. TRMs and CAFS are involved in regulating the formation of the premetastatic niche. CAFs secrete proteases mediating ECM remodeling and CSF1 supporting the growth of TRMs and the recruitment of monocytes via CSF1R. Chemokine- and cytokine-mediated recruitment of inflammatory monocytes promotes vascular permeability and extravasation of migrating cancer cells at the premetastatic niche. Local TRMs, such as alveolar macrophages (AMs) in the lung, Kupffer cells (KCs) in the liver and microglia in the brain, are derived from embryonic hematopoietic organs and are involved in regulating the premetastatic niche, supporting the growth of CAFs and chemokine-mediated recruitment of migrating cancer cells escorted by inflammatory monocytes. After egress from the BM, BM-derived monocytes, M-MDSCs and PMN-MDSCs are recruited to the metastasis sites through chemotactic factors produced by cancer cells, CAFs and TRMs. TRMs are the first to be subject to the effects of cancer-produced soluble factors; they undergo early inflammatory changes and assist in the recruitment of BM-derived monocytes, contributing to the generation of TAMs and fostering formation of the premetastatic niche. Growth factors: M-CSF, GM-CSF; cytokines: IL-6, IL-1, IL-8; chemokines: CCL2, CCL5, CXCL12, CCL4; DAMPs: DNA, RNA, exosomes, uric acid, ATP, metabolites.