cancers Review Restoring the Immunity in the Tumor Microenvironment: Insights into Immunogenic Cell Death in Onco-Therapies Ángela-Patricia Hernández 1 , Pablo Juanes-Velasco 1 , Alicia Landeira-Viñuela 1, Halin Bareke 1,2, Enrique Montalvillo 1, Rafael Góngora 1 and Manuel Fuentes 1,3,* 1 Department of Medicine and General Cytometry Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain; [email protected] (Á.-P.H.); [email protected] (P.J.-V.); [email protected] (A.L.-V.); [email protected] (H.B.); [email protected] (E.M.); [email protected] (R.G.) 2 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Institute of Health Sciences, Marmara University, 34722 Istanbul, Turkey 3 Proteomics Unit, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), 37007 Salamanca, Spain * Correspondence: [email protected]; Tel.: +34-923-294-811 Simple Summary: Since the role of immune evasion was included as a hallmark in cancer, the idea of cancer as a single cell mass that replicate unlimitedly in isolation was dissolved. In this sense, cancer and tumorigenesis cannot be understood without taking into account the tumor microenvironment (TME) that plays a crucial role in drug resistance. Immune characteristics of TME can determine the success in treatment at the same time that antitumor therapies can reshape the immunity in TME. Here, we collect a variety of onco-therapies that have been demonstrated to induce an interesting Citation: Hernández, Á.-P.; immune response accompanying its pharmacological action that is named as “immunogenic cell Juanes-Velasco, P.; Landeira-Viñuela, death”. As this report shows, immunogenic cell death has been gaining importance in antitumor A.; Bareke, H.; Montalvillo, E.; therapy and should be studied in depth as well as taking into account other applications that may Góngora, R.; Fuentes, M. Restoring arise from this immune phenomenon. the Immunity in the Tumor Microenvironment: Insights into Abstract: Immunogenic cell death (ICD) elicited by cancer therapy reshapes the tumor immune Immunogenic Cell Death in Onco-Therapies. Cancers 2021, 13, microenvironment. A long-term adaptative immune response can be initiated by modulating cell 2821. https://doi.org/10.3390/ death by therapeutic approaches. Here, the major hallmarks of ICD, endoplasmic reticulum (ER) cancers13112821 stress, and damage-associated molecular patterns (DAMPs) are correlated with ICD inducers used in clinical practice to enhance antitumoral activity by suppressing tumor immune evasion. Approaches Academic Editor: Alberto Anel to monitoring the ICD triggered by antitumoral therapeutics in the tumor microenvironment (TME) and novel perspective in this immune system strategy are also reviewed to give an overview of the Received: 23 April 2021 relevance of ICD in cancer treatment. Accepted: 4 June 2021 Published: 5 June 2021 Keywords: immunogenic cell death; DAMPs; apoptosis; necroptosis; autophagy; tumor microenvi- ronment; natural products; chemotherapy; ICD inducers; immunotherapy Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Since the establishment of tumorigenesis as a complex network of pathophysiological processes, cancer cell biology cannot be studied without taking into account the surround- ing elements (e.g., blood vessels, immune cells, and extracellular matrix). Tumor cells Copyright: © 2021 by the authors. have acquired mechanisms to hinder anti-tumor immunity. The tumor’s ability to evade Licensee MDPI, Basel, Switzerland. the immune system is one of the steps that have been considered necessary for tumor This article is an open access article establishment and has been included in multi-step processes that have been identified as distributed under the terms and conditions of the Creative Commons “hallmarks of cancer” proposed by Hanahan and Weinberg [1]. The role of immune evasion Attribution (CC BY) license (https:// was included as a hallmark when the idea of cancer as a single cell mass that replicates creativecommons.org/licenses/by/ unlimitedly in isolation was dissolved (Figure1). Rather, it was accepted that a set of 4.0/). normal cells that are recruited to the tumor or that are altered by the tumor to form the Cancers 2021, 13, 2821. https://doi.org/10.3390/cancers13112821 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 31 Cancers 2021, 13, 2821 2 of 30 that a set of normal cells that are recruited to the tumor or that are altered by the tumor to form the tumor-associated stroma, were pivotal for tumor establishment and progression. tumor-associated stroma, were pivotal for tumor establishment and progression. Therefore, Therefore, the cancer cell and tumorigenesis cannot be understood without taking into the cancer cell and tumorigenesis cannot be understood without taking into account the account the tumor microenvironment (TME) [2]. In-depth understanding of molecular signalingtumor and microenvironment extracellular interactions (TME) invo [2].lved In-depth in these understanding processes allows of the molecular develop- signaling and ment extracellularof novel therapies interactions that include involved conventional in these intracellular processes targets allows as the well development as novel of novel approachestherapies to modulate that include the TME. conventional intracellular targets as well as novel approaches to modulate the TME. Figure 1. The immune system within the cancer hallmarks plays a pivotal role in understanding of the TME. Figure 1. The immune system within the cancer hallmarks plays a pivotal role in understanding Treatment resistance remainsof the an TME. important challenge in cancer therapy. Drug resis- tance can be intrinsic due to the presence of mutations that inactivate its potential molecular Treatment resistance remains an important challenge in cancer therapy. Drug re- targets [3]. However, extrinsic resistance of the tumor cells can be promoted by the tumor sistance can be intrinsic due to the presence of mutations that inactivate its potential mo- surrounding. As stated before, tumors are surrounded by a high density of elements lecular targets [3]. However, extrinsic resistance of the tumor cells can be promoted by the tumorsuch surrounding. as extracellular As stated matrix, before, aberrant tumors are vasculature, surrounded and by stromaa high density cells. Withinof ele- this cellular mentscomponent such as extracellular surrounding matrix, the aberrant tumor, vasculature, tumor-infiltrating and stroma cells cells. are Within of special this cel- interest because lular componentof their contradictory surrounding roles the tumor, in immunomodulation tumor-infiltrating cells of tumorare of special progression. interest Whilebe- some cell causepopulations of their contradictory boost tumorigenic roles in immu factors,nomodulation others can of restore tumor immunosurveillance progression. While against the some tumors.cell populations In TME, boost the balancetumorigenic is tilted factors, towards others the can activation restore immunosurveillance of tumor survival-promoting againstelements the tumors. that In enable TME, the tumor balance immune is tilted evasion towards [ the4]. Therefore,activation of therapies tumor survival- that target the im- promotingmunosuppressive elements that enable environment tumor immune in the TMEevasion has [4]. the Therefore, potential therapies to unlock that the tar- power of the get theimmune immunosuppressive system against environment tumor cells. in the TME has the potential to unlock the power of the immune system against tumor cells. 2. Cancer Immunoediting, TME, and Immunogenic Cell Death 2. Cancer Immunoediting, TME, and Immunogenic Cell Death Interactions between the immune system and the tumor, even before the onset of the Interactionsclinical signs between of a tumor, the immune are well system characterized. and the tumor, This even process before encompasses the onset of the different steps clinicalthat signs have of a been tumor, termed are well jointly characteri as immunoeditingzed. This process [ 5encompasses]. Cancer immunoediting different steps defines the that have been termed jointly as immunoediting [5]. Cancer immunoediting defines the interaction between immune cells and tumor cells that can result in either elimination of interaction between immune cells and tumor cells that can result in either elimination of the tumor, an equilibrium state where the tumor is latent or generation of tumor cell popu- the tumor, an equilibrium state where the tumor is latent or generation of tumor cell pop- ulationslations that are that able are to able survive to survive in immunoco in immunocompetentmpetent hosts [6]. First, hosts pre-tumoral [6]. First, pre-tumoralchanges changes are detectedare detected and neutralized and neutralized by the innate by the an innated adaptative and adaptative immune system immune in the system step in the step namednamed “elimination”. “elimination”. In the “equilibrium” In the “equilibrium” phase, the phase, tumor is the not tumor completely is not eliminated; completely eliminated; however,however, it is kept it is under kept undercontrol control by the byimmune the immune system so system that it so doesn’t that it become doesn’t clini- become clinically cally detectable. Finally, Finally, tumors tumors develop develop an editing an editing process process where where immunogenic immunogenic tumor tumor cells