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Simple Summary: Epithelial cancers, such as lung, breast, and colon cancers, have high mortality rates because of their ability to spread across multiple organs in the body. Besides the standard of care which includes chemotherapy and radiotherapy, approaches directed to use patient's own immune responses against the disease called immunotherapies have emerged as a powerful treatment option. In the past 10 years, immune checkpoint blockade, a form of immunotherapy which either stimulates or removes the breaks of the immune response against cancer, is having the largest impact in the clinic. However epithelial cancers are commonly either naturally resistant or develop resistance to these types of treatments. Hence, there is an urgent need to boost the effectiveness of immune checkpoint blockers. Small molecule inhibitors are chemical molecules which are specifically designed to target important cancer proteins and unlike chemotherapy, typically have manageable toxicity. These inhibitors have shown good efficacy in reducing tumour growth but more recently, they have been shown to enhance the performance of immune cells in eliminating cancers. In this review, we have focused on tactical usage of small molecule inhibitors to boost the efficacy of immune checkpoint blockers. We believe our review will pave the way for novel research combining the two therapeutic modalities. Immune checkpoint blockade (ICB) is now standard of care for several metastatic epithelial cancers and prolongs life expectancy for a significant fraction of patients. A hostile tumor microenvironment (TME) induced by intrinsic oncogenic signaling induces an immunosuppressive niche that protects the tumor cells, limiting the durability and efficacy of ICB therapies. Addition of receptor tyrosine kinase inhibitors (RTKi) as potential modulators of an unfavorable local immune environment has resulted in moderate life expectancy improvement. Though the combination strategy of ICB and RTKi has shown significantly better results compared to individual treatment, the benefits and adverse events are additive whereas synergy of benefit would be preferable. There is therefore a need to investigate the potential of inhibitors other than RTKs to reduce malignant cell survival while enhancing anti-tumor immunity. In the last five years, preclinical studies have focused on using small molecule inhibitors targeting cell cycle and DNA damage regulators such as CDK4/6, CHK1 and poly ADP ribosyl polymerase (PARP) to selectively kill tumor cells and enhance cytotoxic immune responses. This review provides a comprehensive overview of the available drugs that attenuate immunosuppression and overcome hostile TME that could be used to boost FDA-approved ICB efficacy in the near future. [ABSTRACT FROM AUTHOR]