Targeting the Tumor Microenvironment for Improving Therapeutic Effectiveness in Cancer Immunotherapy: Focusing on Immune Checkpoint Inhibitors and Combination Therapies

Abstract

Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy.

Tumor metastasis: Mechanistic insights and therapeutic interventions

“…With the deepening understanding of mechanisms of tumorigenesis and metastasis in recent years, a plethora of treatment approaches, including targeted therapy and immunotherapy have been established. 13 , 14 , 15 However, the underlying mechanisms of cancer metastasis are not yet fully understood, and the strategies for preventing and inhibiting cancer metastasis are also limited.…”

Exploiting the STAT3 Nexus in Cancer-Associated Fibroblasts to Improve Cancer Therapy

“…However, it is now appreciated that non-malignant cells within the tumor microenvironment (TME) play equally important roles in driving the development and progression of tumors (13,14). Owing to the complexity and heterogenous nature of tumors, different approaches have been employed to target various facets of the TME in an effort to modulate the extracellular matrix (ECM), cytokines that drive chronic inflammation, hypoxia and angiogenesis (reviewed in (14)(15)(16)(17)(18)(19)(20)). In addition, other strategies home into targeting the cellular components of the TME including stromal and immune cells.…”

Miniaturized and multiplexed high-content screening of drug and immune sensitivity in a multichambered microwell chip

“…Data-driven searches for new biomarkers based on sequencing or proteomics data will not replace functional test but instead generate new hypotheses that will require in vitro validation, increasing the need for high-content screening with readouts based on functional responses. One area where it has proven challenging to predict patient responses using biomarkers is immunotherapy ( Ameratunga et al., 2018 ; Chyuan et al., 2021 ; Fujii et al., 2018 ; Maleki Vareki, 2018 ; Maleki Vareki et al., 2017 ), where most treatments show significant percentages of non-responders across multiple cancer types ( Borcoman et al., 2019 ; Sharma et al., 2017 ). Therefore, development of new methods for validating individualized treatments is urgently needed to personalize immunotherapy and to advance precision medicine.…”