This special issue of Seminars in Immunopathology is entitled “Novel immunotherapeutic combinations moving forward: The modulation of the immunosuppressive microenvironment,” and focuses on the role and modulation of the tumor microenvironment (TME) in cancer. Immunotherapy is currently a major part of cancer treatment, and it is leading to changes in treatment strategies for most, if not all, cancers. Novel immunotherapies and combinations for treating advanced cancers are being approved at a swift pace. However, the success of immunotherapy is limited by the many immunosuppressive features of the TME. Tumor cells do not exist as isolated units; they are surrounded by a variety of cells and the extracellular matrix, which, taken together, constitute the TME. The interactions between cancer cells and their surroundings essentially dictate the outcome of patients. Immune cells of the TME are often highjacked to promote tumor growth, invasion, and immune escape. In this issue, leading experts in the field describe the key cells responsible for the immunosuppressive environment; they present and discuss novel immunotherapeutic combinations that aim to target and modulate the TME. This issue also presents novel, cutting-edge technologies for studying cancer immunity and improving treatment to ensure the continuous and greater success of anti-cancer immunotherapy.

The TME consists of many different cells, including myeloid cells, which constitute a large part of the TME. Immune-suppressive myeloid cells comprise a heterogenous population of cells that include tumor-associated macrophages (TAMs), neutrophils, dendritic cells, and monocytes. In this issue, De Sanctis and co-authors provide an overview of therapeutic possibilities for targeting myeloid cells in cancer [1]. The authors extensively describe the emerging strategies that may modulate the functional activity of tumor-supporting myeloid cells to subvert their accumulation, recruitment, survival, and functions. They provide a comprehensive analysis of the potential mechanisms and regulators involved in the development and polarization of myeloid cells with pro-tumoral activity. Moreover, they describe many potential targets expressed by myeloid cells, which can be approached to develop innovative cancer treatments. Among the many different types of myeloid cells, especially TAMs are key regulators of immunosuppression. Sadhukhan and Seiwert further describe the role of TAMs in the TME and discuss in detail the mechanisms by which TAMs regulate immune responses [2]. They further summarize the current status of the development of therapeutics that targets TAMs and tumor metabolism.

Cancer-associated fibroblasts (CAFs) are another essential component of the TME. Increasing evidence has shown that CAFs comprise a major player in both tumor progression and in therapy response. In the current issue, Maia et al. highlight the current knowledge about the role of CAFs in the TME, with particular focus on the ability of CAFs to modulate immune activity [3]. Here, the authors provide an excellent overview of the current knowledge of CAF-immune cell interactions in cancer. They review the main mechanisms in cancer immune therapy, and they describe in detail how targeting CAFs can improve the efficacy of anti-cancer immune therapy.

Many different anti-cancer immune therapies are currently being developed, including checkpoint inhibitors, vaccines, and cellular therapies. One class of cellular therapies comprises chimeric antigen receptor (CAR)-modified T cells. These therapies have achieved particularly impressive results in distinct blood cancer indications. However, their application beyond hematology has been underwhelming, particularly in solid oncology. The TME is a major reason for this lack of success, because the TME functionally suppresses, restricts, and excludes adoptive immune cells. The chapter by Huyhn et al. in this special issue summarizes current and novel strategies for reshaping the TME to optimize and improve CAR-modified T-cell treatments [4]. This is followed by the chapter of Espie and Donnadieu, who describe how real-time imaging has contributed to our understanding of the biology of CAR-modified T cells [5]. Until recently, the characterization of CAR-modified T cells has been mainly based on flow cytometry and whole-transcriptome profiling. These approaches have been valuable in determining the intrinsic elements that condition T cells to be able to proliferate and expand. However, these measures did not consider the spatial and kinetic aspects of T-cell responses. Thus, Espie and Donnadieu describe important concepts that have emerged from imaging-based studies, such as the multi-killing potentials of CAR-modified T cells. They also highlight how imaging techniques, combined with other tools, can solve the remaining unresolved questions in the field of engineered T cells.

In general, further therapeutic advancement in immunotherapy requires an in-depth understanding of the interplay in the TME between immune cells and tumors. Franciosa et al. describe recent advances in mass spectrometry (MS)-based proteomics and how this approach is used to study pre-clinical and clinical research findings in the context of tumor immunity and cancer immunotherapy [6]. The MS-based proteomics technique facilitates the analysis of the many cellular interactions and reactions in the TME, including post-translational modifications, subcellular protein localization, cell signaling, and protein–protein interactions.

The present issue finishes with some timely reviews that describe novel and highly interesting combination immunotherapies. For example, vaccine approaches for modulating the immunosuppressive TME are emerging as an attractive, novel possibility in anti-cancer immunotherapy. Andersen describes those approaches and defines “tumor microenvironment antigens” (TMAs) [7]. TMAs are antigens expressed on different cells in the TME, including tumor cells and regulatory immune cells, which can be recognized by anti-regulatory T cells (anti-Tregs). These TMA-specific T cells might directly kill both tumor cells and other regulatory cells. In addition, they might reprogram regulatory cell populations by releasing pro-inflammatory cytokines into an immunosuppressive microenvironment. Immune modulatory vaccines offer an attractive approach for combinatorial therapy with other forms of immunotherapy, including checkpoint blockade, cellular therapy, or traditional cancer vaccines. The addition of immune modulatory vaccines to such treatment modalities will most likely increase the number of patients that can benefit from immunotherapy.

Next, Bezu et al. summarize the novel links between local anesthetics and anti-cancer immune responses [8]. They discuss this novel combination treatment and how recent advances in oncolytic local anesthetics can improve anti-cancer immunotherapy. In surgical clinics, anesthetics are routinely used in different operations for patients with resectable solid tumors. With advances in neoadjuvant immunotherapy for different types of cancers, key questions have been raised concerning the abscopal systemic immune response and the rapidly advancing development of combinatory immunostimulating therapies, including local oncolytic treatment.

Melief et al. focus on cancers that are caused by human papillomavirus (HPV) and how to use therapeutic vaccinations with other forms of immunotherapy to target either premalignant conditions or different stages of cancer [9]. Targeting premalignant conditions is an elegant way to avoid the negative effects of a highly immunosuppressive TME. Their review focuses on the successful use of a therapeutic vaccine composed of synthetic long peptides (SLP) that cover the complete sequence of the two oncogenic proteins, E6 and E7, of HPV type 16 (HPV16) in patients with premalignant disease. The authors describe how a combination treatment was required, due to the immunosuppressive TME in established HPV16 + cancer. However, the combination of the vaccine with either the standard-of-care chemotherapy or with immune checkpoint inhibition (with anti-PD-1) led to interesting clinical effects in patients with late-stage recurrent or metastatic cancers.

Overall, the current issue provides the reader with an up-to-date summary of the current knowledge regarding the most important cells responsible for the immunosuppressive features of the TME. Furthermore, it describes some highly interesting, novel combination therapies that have shown very interesting, clinical anti-cancer responses by modulating or circumventing the immune-hostile TME.