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• TGF-β promotes anti-tumor immune cell exclusion and dysfunction. • TGF-β and PD-L1 show independent but complementary immunosuppressive potentials. • Anti-PD-L1/TGF-βRII trap agents enable PD-L1 saturation and TGF-β sequestration. • M7824 is more effective in PD-L1high or immune-excluded tumors. Immune checkpoint inhibitor (ICI) therapy suffers from tumor resistance and relapse in majority of patients due to the suppressive tumor immune microenvironment (TIME). Advances in the field have brought about development of fusion proteins able to target two signaling simultaneously and to exert maximal anti-cancer immunity. Bispecific inhibitors of transforming growth factor (TGF)-β signaling and programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are developed to reduce the rate of relapse and to achieve durable anti-cancer therapy. TGF-β is well-known for its immunosuppressive activity, and it takes critical roles in promotion of all tumor hallmarks. Bispecific anti-PD-(L)1/TGF-β inhibitors reinvigorate effector activity of CD8+ T and natural killer (NK) cells, hamper regulatory T cell (Treg) expansion, and increase the density of anti-tumor type 1 macrophages (M1). Responses to the bispecific approach are higher compared with solo anti-PD-(L)1 or TGF-β targeted therapy, and are seemingly more pronounced in human papillomavirus (HPV)+ patients. High expression of PD-L1 or immune-excluded phenotype in a tumor can also be markers of better response to the bispecific strategy. Besides, anti-PD-(L)1/TGF-β inhibitor therapy can be used safely with other therapeutic modalities including vaccination, radiation and chemotherapy. [ABSTRACT FROM AUTHOR]

• Aberrant B7x expression occurs in human cancers. • B7x preferentially expresses in APCs and tumor cells. • B7x promotes immune escape and associates with poor tumor cell differentiation. • B7x expression inversely correlates with PD-L1 expression profile. • B7x receptor is co-expressed with PD-1 on CD8+ T cells. • Anti-B7x can be used synergistically with anti-PD-(L)1 or anti-CTLA-4. • Bispecific inhibitors against B7x and other regulatory molecules are underway. B7x (also called B7-H4) is a co-inhibitory molecule of B7 family that is highly expressed in non-inflamed or cold cancers, and its aberrant expression is contributed to cancer progression and poor outcomes. B7x preferentially expresses on antigen-presenting cells (APCs) and in tumor cells, and it acts as an alternative anti-inflammatory immune checkpoint for hampering peripheral immune responses. Augmented infiltration of immunosuppressive cells, reduced proliferation and effector function of CD4+ and CD8+ T cells, and increased generation of regulatory T cells (Tregs) are outcomes of increased B7x activity in cancer. Evaluation of B7x in sera can be exploited as an effective biomarker of response in cancer patients. B7x overexpression generally occurs in programmed death-ligand 1 (PD-L1)- cancers and is involved in tumor resistance to anti-programmed death-1 (PD-1), anti-PD-L1 or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) therapy. Co-expression of B7x receptor with PD-1 on CD8+ T cells has made the anti-B7x a fruitful approach for reinvigoration of the functionality of exhausted T cells and is served as a complementary regimen in patients who are irresponsive to the common immune checkpoint inhibitor (ICI) therapy. An advance in the field is the development of bispecific antibodies against B7x with other regulatory molecules within tumor microenvironment (TME). [ABSTRACT FROM AUTHOR]

• Competition for IL-2 among immune cells will reduce the amount of IL-2 in TME. • High-dose IL-2 therapy is more effective in metastatic RCC than metastatic melanoma. • The activity of high-dose IL-2 therapy is attenuated by VEGF, IL-2Rα and MAGE-A3. • Toxicities related to the high-dose IL-2 may sometimes be life-threatening. • The current focus is over engineering pegylated IL-2 and IL-2 variants with selective activities. Interleukin (IL)-2 is a pleiotropic cytokine that displays opposing activities on immune system acting either in favor of or against cancer progression. Advanced/metastatic melanoma and renal cell carcinoma (RCC) are the two types of cancers that included most studies implemented for assessing the role of high-dose IL-2 therapy. The use of high-dose IL-2 therapy can, however, increase the rate of toxicities and interferes with the activity of endothelial cells (ECs) and effector T cells in tumor microenvironment (TME). This implies the need for adjusting strategies related to the cytokine therapy, such as suppressing signals that are interfering with the activity of this cytokine or the use of engineered IL-2 variants. The focus of this review is to discuss about pros and cons related to the IL-2 therapy and propose strategies to increase the efficacy of therapy. The outcomes of this literature will call for application of variants of IL-2 engineered to represent higher half-life and efficacy, and are more safe in the area of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumors. However, it has been shown that radiotherapy alone is unable to completely eradicate some tumors and could be associated with a high possibility of tumor recurrence. To date, various experimental and clinical studies have been conducted to explore some efficient targets within tumor microenvironment (TME) to enhance tumor response to radiotherapy; thus help eliminate or eradicate tumors. Although targeting DNA damage responses (DDRs) is associated with severe toxicities, studies in recent decade suggest that inhibition of some apoptosis/survival targets within TME is promising. This is also associated with changes in the numbers of T regulatory cells (Tregs) and cytotoxic T lymphocytes (CTLs). The inhibition of cyclooxygenase-2 (COX-2), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) and vascular endothelial growth factor (VEGF) have also shown promising results. The combination of receptor tyrosine kinase (RTK) inhibitors with radiotherapy is interesting as well as the clinical use of some drugs and antibodies. Epidermal growth factor receptor (EGFR) inhibitors are the most common RTK inhibitors. Some clinical trials in recent years have shown very interesting results for immune checkpoint inhibitors (ICIs), especially programmed death-ligand 1 (PD-L1) and CTLs–associated antigen 4 (CTLA-4) inhibitors. It has been suggested that administration of ICIs during or after hypofractionated radiotherapy could lead to best results. In this review, we explain TME response to radiotherapy and potential targets for sensitization of cancer cells to radiotherapy. • A high dose of ionizing radiation is more efficient to release immune antigen stimulators. • The balance between immunogenic vs tolerogenic cell death plays a key role in the fate of radiotherapy. • Targeting apoptosis resistant mediators is the most common aim for sensitization of cancer cells to radiotherapy. • MAPKs, NFkB, COX-2, PI3K, mTOR, EGFR, HIF-1, PDL-1 and CTLA-4 are the most interesting targets for induction of apoptosis. • Immune system responses to radiotherapy can be change by radiation dose and time. [ABSTRACT FROM AUTHOR]

[Display omitted] • IDO1 induces immune tolerance within TME. • Serum profiling of IDO1 metabolites is of prognostic value. • IDO1 upregulation occurs after ICI therapy. • IDO1 inhibitors can be used safely with ICI therapy. • Epacadostat plus ICI renders promising clinical responses. • Clinical efficacy of anti-PD-L1/IDO inhibitor vaccination is promising. Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper. [ABSTRACT FROM AUTHOR]