diff --git a/Misc/NEWS.d/next/Tests/2022-06-10-21-18-14.gh-issue-84461.9TAb26.rst b/Misc/NEWS.d/next/Tests/2022-06-10-21-18-14.gh-issue-84461.9TAb26.rst
new file mode 100644
index 00000000000..7cdf5bee721
--- /dev/null
+++ b/Misc/NEWS.d/next/Tests/2022-06-10-21-18-14.gh-issue-84461.9TAb26.rst
@@ -0,0 +1,2 @@
+``run_tests.py`` now handles cross compiling env vars correctly and pass
+``HOSTRUNNER`` to regression tests.
diff --git a/Tools/scripts/run_tests.py b/Tools/scripts/run_tests.py
index 48feb3f778e..8dbcade9238 100644
--- a/Tools/scripts/run_tests.py
+++ b/Tools/scripts/run_tests.py
@@ -8,7 +8,9 @@ simply passing a -u option to this script.
 """
 
 import os
+import shlex
 import sys
+import sysconfig
 import test.support
 
 
@@ -19,15 +21,37 @@ def is_multiprocess_flag(arg):
 def is_resource_use_flag(arg):
     return arg.startswith('-u') or arg.startswith('--use')
 
+def is_python_flag(arg):
+    return arg.startswith('-p') or arg.startswith('--python')
+
 
 def main(regrtest_args):
     args = [sys.executable,
             '-u',                 # Unbuffered stdout and stderr
             '-W', 'default',      # Warnings set to 'default'
             '-bb',                # Warnings about bytes/bytearray
-            '-E',                 # Ignore environment variables
             ]
 
+    cross_compile = '_PYTHON_HOST_PLATFORM' in os.environ
+    if (hostrunner := os.environ.get("_PYTHON_HOSTRUNNER")) is None:
+        hostrunner = sysconfig.get_config_var("HOSTRUNNER")
+    if cross_compile:
+        # emulate -E, but keep PYTHONPATH + cross compile env vars, so
+        # test executable can load correct sysconfigdata file.
+        keep = {
+            '_PYTHON_PROJECT_BASE',
+            '_PYTHON_HOST_PLATFORM',
+            '_PYTHON_SYSCONFIGDATA_NAME',
+            'PYTHONPATH'
+        }
+        environ = {
+            name: value for name, value in os.environ.items()
+            if not name.startswith(('PYTHON', '_PYTHON')) or name in keep
+        }
+    else:
+        environ = os.environ.copy()
+        args.append("-E")
+
     # Allow user-specified interpreter options to override our defaults.
     args.extend(test.support.args_from_interpreter_flags())
 
@@ -38,16 +62,30 @@ def main(regrtest_args):
     if sys.platform == 'win32':
         args.append('-n')         # Silence alerts under Windows
     if not any(is_multiprocess_flag(arg) for arg in regrtest_args):
-        args.extend(['-j', '0'])  # Use all CPU cores
+        if cross_compile and hostrunner:
+            # For now use only one core for cross-compiled builds;
+            # hostrunner can be expensive.
+            args.extend(['-j', '1'])
+        else:
+            args.extend(['-j', '0'])  # Use all CPU cores
     if not any(is_resource_use_flag(arg) for arg in regrtest_args):
         args.extend(['-u', 'all,-largefile,-audio,-gui'])
+
+    if cross_compile and hostrunner:
+        # If HOSTRUNNER is set and -p/--python option is not given, then
+        # use hostrunner to execute python binary for tests.
+        if not any(is_python_flag(arg) for arg in regrtest_args):
+            buildpython = sysconfig.get_config_var("BUILDPYTHON")
+            args.extend(["--python", f"{hostrunner} {buildpython}"])
+
     args.extend(regrtest_args)
-    print(' '.join(args))
+
+    print(shlex.join(args))
     if sys.platform == 'win32':
         from subprocess import call
         sys.exit(call(args))
     else:
-        os.execv(sys.executable, args)
+        os.execve(sys.executable, args, environ)
 
 
 if __name__ == '__main__':
diff --git a/configure b/configure
index 5c85360b303..01d599da29f 100755
--- a/configure
+++ b/configure
@@ -6782,7 +6782,7 @@ else
 fi
      ;; #(
               WASI/*) :
-    HOSTRUNNER='wasmtime run --env PYTHONPATH=$$(realpath --relative-to $(abs_srcdir) $(abs_builddir))/$$(cat pybuilddir.txt) --mapdir /::$(srcdir) --' ;; #(
+    HOSTRUNNER='wasmtime run --env PYTHONPATH=/$(shell realpath --relative-to $(abs_srcdir) $(abs_builddir))/$(shell cat pybuilddir.txt) --mapdir /::$(srcdir) --' ;; #(
   *) :
     HOSTRUNNER=''
    ;;
@@ -6792,6 +6792,10 @@ fi
 { $as_echo "$as_me:${as_lineno-$LINENO}: result: $HOSTRUNNER" >&5
 $as_echo "$HOSTRUNNER" >&6; }
 
+if test -n "$HOSTRUNNER"; then
+    PYTHON_FOR_BUILD="_PYTHON_HOSTRUNNER='$HOSTRUNNER' $PYTHON_FOR_BUILD"
+fi
+
 { $as_echo "$as_me:${as_lineno-$LINENO}: result: $LDLIBRARY" >&5
 $as_echo "$LDLIBRARY" >&6; }
 
diff --git a/configure.ac b/configure.ac
index 93c198fe1ce..d6639130490 100644
--- a/configure.ac
+++ b/configure.ac
@@ -1492,13 +1492,18 @@ then
     dnl TODO: support other WASI runtimes
     dnl wasmtime starts the proces with "/" as CWD. For OOT builds add the
     dnl directory containing _sysconfigdata to PYTHONPATH.
-    [WASI/*], [HOSTRUNNER='wasmtime run --env PYTHONPATH=$$(realpath --relative-to $(abs_srcdir) $(abs_builddir))/$$(cat pybuilddir.txt) --mapdir /::$(srcdir) --'],
+    [WASI/*], [HOSTRUNNER='wasmtime run --env PYTHONPATH=/$(shell realpath --relative-to $(abs_srcdir) $(abs_builddir))/$(shell cat pybuilddir.txt) --mapdir /::$(srcdir) --'],
     [HOSTRUNNER='']
   )
 fi
 AC_SUBST([HOSTRUNNER])
 AC_MSG_RESULT([$HOSTRUNNER])
 
+if test -n "$HOSTRUNNER"; then
+  dnl Pass hostrunner variable as env var in order to expand shell expressions.
+  PYTHON_FOR_BUILD="_PYTHON_HOSTRUNNER='$HOSTRUNNER' $PYTHON_FOR_BUILD"
+fi
+
 AC_MSG_RESULT($LDLIBRARY)
 
 # LIBRARY_DEPS, LINK_PYTHON_OBJS and LINK_PYTHON_DEPS variable